A total of 3501 articles were identified using database searching, and 3336 were recorded after duplicates removal. 2840 were excluded after screening of title/abstract, 280 were finally excluded, and 8 articles were excluded during data extraction. These exclusions were primarily due to factors such as non-conformity with the study focus, insufficient methodological rigor, or data that did not align with the research questions. Finally, 208 articles were included as references. PRISMA Flow Diagram is Fig 1.
Interactions Between Signaling Pathways and mRNA Export Mechanisms:
- Nuclear Transport Pathway
The Nuclear Transport Pathway plays a fundamental role in regulating mRNA export during embryonic development, ensuring that specific mRNAs are properly translocated from the nucleus to the cytoplasm. This regulation is critical for gene expression control and the coordination of cellular processes, such as proliferation, differentiation, and maintaining stem cell potency. In embryonic stem cells (ESCs), modulation of mRNA export by the nuclear transport machinery can significantly impact pluripotency and lineage-specific gene expression [11, 12].
Molecular Mechanisms of Nuclear Transport in mRNA Export:
The nuclear transport pathway operates through nuclear pore complexes (NPCs), which are essential for the bidirectional movement of macromolecules, including mRNA, between the nucleus and cytoplasm. The export of mRNA from the nucleus to the cytoplasm is primarily mediated by transport receptors known as karyopherins, specifically exportins, which function alongside RNA-binding proteins (RBPs) and other export factors. This pathway is highly regulated, ensuring that only fully processed and mature mRNAs are exported from the nucleus [12, 13].
A crucial component in this process is Nuclear Export Factor 1 (NXF1), the main mRNA export receptor in eukaryotic cells. NXF1 binds to mature mRNAs through adaptor proteins such as ALYREF (Aly/REF export factor) and the THOC complex, which is a part of the TREX complex. By interacting with nucleoporins within the NPC, NXF1 transports mRNA through the NPC to the cytoplasm. This interaction is essential for the efficient translocation of mRNAs, linking mRNA processing with export and enabling the timely response to cellular signals [13, 14].
The TREX (Transcription Export) complex plays a crucial role in coupling transcription and mRNA processing with export. Comprising components like THOC5, THOC2, and ALYREF, the TREX complex binds to spliced mRNA, facilitating its export by recruiting NXF1. TREX is critical for recognizing properly processed mRNAs, ensuring that only mRNAs that have undergone accurate processing are selected for export. This mechanism safeguards against the export of defective mRNAs, maintaining cellular homeostasis and ensuring fidelity in gene expression [14, 15].
Nuclear pore complexes (NPCs), which are composed of proteins called nucleoporins, function as selective gates that regulate mRNA export. These NPCs interact with the mRNA export machinery, guiding the translocation of mRNAs across the nuclear envelope. Among the nucleoporins, NUP98 is known for its interactions with export machinery components, playing a significant role in facilitating mRNA export. This interaction underscores the importance of NPCs as more than mere structural entities but as active participants in the regulation of nuclear export [15, 16].
Although Ran GTPase is more prominently involved in protein import and export, it is vital for maintaining the gradient necessary for directional nuclear transport. Ran-GTP specifically contributes to the release of export factors such as NXF1 once mRNA reaches the cytoplasm. This GTPase-driven mechanism ensures the recycling of export factors and sustains the continuous export of mRNAs, highlighting the interplay between various components of the nuclear transport pathway in regulating gene expression [16, 17].
Interaction with mRNA Export Machinery:
During embryonic development, the export of specific mRNAs crucial for stem cell potency and differentiation is tightly regulated by a coordinated network of molecular components. This regulation ensures that mRNAs essential for developmental processes are accurately transcribed, processed, and exported. Co-transcriptional recruitment of export factors to nascent mRNA transcripts plays a key role in this process. Components of the mRNA export machinery, such as the TREX complex, are recruited during transcription to facilitate proper mRNA packaging and processing. RNA-binding proteins (RBPs), including SR proteins, associate with spliced mRNAs, ensuring that the mRNAs are appropriately packaged and rendered export-competent [17, 18].
Splicing and quality control mechanisms are vital for maintaining the fidelity of mRNA export. Proper splicing of mRNAs allows recognition by the export machinery, ensuring that only correctly processed mRNAs are exported to the cytoplasm. Aberrantly processed or unspliced mRNAs are retained in the nucleus, which prevents their export and acts as a quality control step. The Exon Junction Complex (EJC) is deposited on spliced mRNAs and is critical for the recruitment of export factors. This complex not only facilitates the recognition of export-ready mRNAs but also directs them to the nuclear pore complex (NPC) for translocation to the cytoplasm. This coordinated system underscores the importance of stringent quality control during mRNA export, which is essential for proper stem cell function and differentiation during development [18, 19].
Role in Embryonic Stem Cell Differentiation and Potency:
The regulation of mRNA export through the nuclear transport pathway plays a crucial role in embryonic stem cell (ESC) behavior, particularly by influencing the expression of pluripotency factors and lineage-specific genes. This pathway ensures that the mRNAs required for maintaining stem cell properties and for initiating differentiation are properly processed and exported, enabling precise control over stem cell function [19, 20].
ESCs rely on core transcription factors such as Oct4, Sox2, and Nanog to maintain pluripotency. These factors are subject to tight regulation at both the transcriptional and post-transcriptional levels, with mRNA export being a key step in this process. The export of mRNAs encoding these pluripotency factors must be precisely controlled to maintain the appropriate cytoplasmic levels needed for ESC self-renewal and maintenance. Any dysregulation in mRNA export could lead to altered levels of these factors, potentially compromising ESC maintenance and the ability to self-renew [20, 21].
As ESCs begin to differentiate and commit to specific lineages, the export of mRNAs that encode lineage-specific factors becomes essential. For instance, mRNAs encoding Brachyury, which is associated with mesoderm formation, or Gata6, which is involved in endodermal differentiation, are selectively exported as ESCs transition to their respective lineages. This selective regulation of mRNA export ensures that genes essential for lineage commitment are expressed at the correct developmental stage. Disruption in this selective export process can impair differentiation, potentially resulting in developmental abnormalities. Thus, mRNA export is not only critical for the maintenance of pluripotency but also for the timely expression of lineage-specific genes during differentiation [21, 22].
Modulation of mRNA Export and its Effects on ESCs:
Targeted manipulation of the nuclear transport pathway can significantly alter mRNA export efficiency in embryonic stem cells (ESCs), thereby impacting cell behavior and fate decisions. Adjustments to the function of export factors or nuclear pore components can influence which mRNAs reach the cytoplasm, affecting the balance between pluripotency and differentiation [22, 23].
Inhibition of mRNA export is one approach to altering mRNA availability within ESCs. By inhibiting export factors like NXF1 or elements of the TREX complex, specific mRNAs, especially those associated with pluripotency or differentiation, may be retained in the nucleus. For example, knocking down NXF1 in ESCs could reduce the export of mRNAs that encode pluripotency factors, potentially triggering premature differentiation or impairing the cells' capacity for self-renewal. Such interventions provide insight into the regulatory mechanisms that govern stem cell maintenance and highlight the importance of controlled mRNA export in preserving ESC identity [22, 23].
Enhancing mRNA export can have the opposite effect, increasing the cytoplasmic presence of mRNAs required for lineage commitment and possibly accelerating differentiation. Overexpressing NXF1 or modifying nuclear pore complexes (NPCs) to boost export activity may facilitate the export of differentiation-related mRNAs, promoting quicker developmental transitions. This approach could be used to control the timing of differentiation by adjusting the export efficiency of mRNAs involved in lineage specification, providing a tool to direct ESC fate in a controlled manner [23, 24].
Regulation of mRNA splicing and export also plays a crucial role in determining export competency. Alterations in spliceosome components or RNA-binding proteins (RBPs) can affect co-transcriptional splicing and, consequently, the export of pre-mRNAs. In ESCs, changes in the function of splicing factors may lead to the selective retention or export of specific mRNAs, influencing differentiation pathways. These dynamics underscore the interconnectedness of mRNA splicing and export in ESCs and their impact on gene expression and developmental potential [24, 25].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export via the nuclear transport pathway has significant downstream effects on various facets of embryonic stem cell (ESC) function, including proliferation, differentiation potential, and overall cellular homeostasis. By controlling which mRNAs are available in the cytoplasm, this pathway directly influences key cellular processes and the maintenance of stem cell properties [25, 26].
Efficient mRNA export is critical for ESC proliferation. The export of mRNAs encoding proteins essential for cell cycle progression, such as cyclins and cyclin-dependent kinases (CDKs), ensures that these proteins are readily available in the cytoplasm. Disruptions in mRNA export can impede the cell cycle, leading to cell cycle arrest or even apoptosis, thereby hindering ESC proliferation. This regulatory control highlights the importance of mRNA export in supporting the rapid cell division characteristic of pluripotent cells [26, 27].
The differentiation potential of ESCs is also modulated by the selective export of mRNAs that encode factors promoting differentiation. By determining which differentiation-promoting mRNAs are exported, the nuclear transport pathway helps guide the transition from a pluripotent state to a lineage-committed state. Manipulating export pathways can either slow down or hasten differentiation, depending on which mRNAs are retained or released into the cytoplasm. This control over mRNA export provides a mechanism for fine-tuning the timing and trajectory of differentiation in ESCs [27, 28].
Beyond proliferation and differentiation, the nuclear transport pathway is essential for overall cellular function and homeostasis in ESCs. The export of mRNAs involved in metabolic processes, stress responses, and signal transduction helps maintain cellular equilibrium. Proper mRNA export is vital for balancing self-renewal and differentiation, ensuring that ESCs can respond dynamically to internal and external signals while maintaining their pluripotent state [28, 29].
Therapeutic and Research Implications:
Given its role in controlling gene expression and cellular differentiation, the nuclear transport pathway represents a potential target for modulating stem cell behavior in therapeutic applications. Manipulating mRNA export could be used to either maintain pluripotency in stem cells or direct them toward specific lineages for regenerative medicine purposes [29, 30].
- PI3K-Akt Signaling Pathway
The PI3K-Akt Signaling Pathway is a critical regulator of various cellular processes, including survival, growth, and metabolism, and it also plays a significant role in regulating mRNA export during embryonic development. This pathway can influence the export of specific mRNAs by interacting with components of the export machinery and RNA-binding proteins. During embryonic stem cell (ESC) differentiation, the modulation of mRNA export by the PI3K-Akt pathway can significantly impact the maintenance of pluripotency and the activation of lineage-specific genes [31, 32].
Molecular Mechanisms of PI3K-Akt in mRNA Export Regulation:
The PI3K-Akt pathway is activated by growth factors and extracellular signals that bind to cell surface receptors, such as receptor tyrosine kinases (RTKs). Upon activation, phosphatidylinositol 3-kinase (PI3K) generates phosphatidylinositol-3,4,5-trisphosphate (PIP3), which subsequently recruits and activates Akt, also known as Protein Kinase B. Once Akt is activated, it phosphorylates a diverse set of downstream targets that govern cell survival, metabolism, and growth. Among these targets are components associated with the mRNA export machinery, implicating the pathway in the regulation of mRNA export dynamics [32, 33].
Akt, once activated, can translocate to the nucleus, where it regulates various proteins involved in mRNA processing and export. A key example is the phosphorylation of SR proteins (serine/arginine-rich proteins), which are known for their roles in splicing and mRNA export. This phosphorylation can influence which mRNAs are selected for export, thereby connecting Akt activity to the control of gene expression through mRNA export pathways [33, 34].
The pathway also impacts mRNA export through mTOR (mechanistic target of rapamycin), which is often considered a downstream component of PI3K-Akt signaling. mTOR regulates the translation machinery and mRNA processing components, affecting export efficiency by modulating the production and stability of proteins in the mRNA export pathway. In this way, mTOR plays a role in linking the PI3K-Akt pathway with both translational control and mRNA export [34, 35].
In addition, eIF4E (Eukaryotic Initiation Factor 4E), a component traditionally linked to translation initiation, is also involved in mRNA export. The activity of eIF4E can be regulated by the PI3K-Akt pathway, which subsequently influences the export of specific mRNAs containing 4E-sensitive motifs. These motifs are commonly associated with cell growth and proliferation, underscoring the pathway's broader role in cellular regulation through its impact on mRNA export and translation [35, 36].
Interaction with mRNA Export Machinery:
The PI3K-Akt pathway influences mRNA export by modulating the activity and expression of RNA-binding proteins (RBPs) and export factors, thereby affecting mRNA selection and export efficiency. This interaction highlights the pathway's role beyond traditional cell survival and growth, as it integrates with nuclear export processes to control gene expression [36, 37].
Akt plays a role in regulating SR proteins and splicing factors, such as SRSF1 (Serine/Arginine-Rich Splicing Factor 1), which participate in both splicing and export of mRNAs. Akt-mediated phosphorylation of these proteins affects their activity, thereby influencing the nuclear export of spliced mRNAs. This impact is particularly significant for mRNAs involved in cell cycle regulation and differentiation, underscoring a key pathway by which Akt modulates gene expression through export [38, 39].
The PI3K-Akt pathway may also interact with components of the TREX (Transcription-Export) Complex, including ALYREF, a factor that links splicing to mRNA export. By regulating TREX activity, the pathway indirectly determines which mRNAs are processed and prepared for export, thereby influencing the selection and efficiency of mRNA export based on cellular needs [38, 40].
In addition, Akt can modulate the transcription of nucleoporins, such as NUP153, which are critical components of the Nuclear Pore Complex (NPC) involved in mRNA export. This regulation helps control the rate and specificity of mRNA transport through NPCs, impacting overall mRNA export efficiency. Through these various interactions, the PI3K-Akt pathway exerts a broad influence on mRNA export, adding another layer of control to cellular growth and differentiation processes [39, 41].
Role in Embryonic Stem Cell Differentiation and Potency:
The PI3K-Akt pathway plays a critical role in embryonic stem cell (ESC) differentiation and potency by regulating the export of mRNAs coding for both pluripotency factors and lineage-specific transcription factors. Through this regulation, the pathway influences key aspects of stem cell fate and developmental potential [40, 41].
In ESCs, the pathway contributes to the maintenance of pluripotency by controlling the export of mRNAs encoding essential factors such as Oct4, Sox2, and Nanog. By facilitating the export and subsequent translation of these mRNAs, the PI3K-Akt pathway helps sustain the intracellular levels of these proteins, which are crucial for self-renewal and the maintenance of pluripotency in stem cells. This regulatory mechanism allows ESCs to retain their undifferentiated state [41, 42].
As ESCs undergo differentiation, the PI3K-Akt pathway adjusts the export of mRNAs encoding transcription factors critical for specific lineage commitments. For instance, the pathway influences the export of mRNAs for factors like GATA4, which is important for endodermal differentiation, and Pax6, which plays a role in ectodermal lineage specification. This selective export of mRNAs enables timely expression changes necessary for lineage commitment and supports the progression of ESCs into specialized cell types during development [42, 43].
Modulation of mRNA Export and Its Effects on ESCs:
Manipulating the PI3K-Akt pathway can significantly impact mRNA export efficiency in embryonic stem cells (ESCs), with substantial consequences for cell behavior and developmental potential. Such targeted interventions reveal insights into the pathway’s role in regulating ESC pluripotency and differentiation [43, 44].
Inhibition of Akt, using small-molecule inhibitors like MK-2206, suppresses the export of specific growth-promoting mRNAs, which may reduce cell proliferation and alter differentiation patterns. By disrupting the export of pluripotency-related mRNAs, Akt inhibition can accelerate differentiation or diminish self-renewal capacity, indicating the pathway's importance in maintaining an undifferentiated state [45, 46].
Conversely, overexpression or activation of Akt enhances the export of mRNAs that promote cell proliferation and inhibit apoptosis, which can reinforce pluripotency and delay differentiation. Enhanced Akt activity might specifically increase the export of mRNAs associated with pluripotency factors, supporting continued self-renewal and maintenance of the undifferentiated state in ESCs [44, 45].
The modulation of downstream components, such as mTOR and eIF4E, also impacts mRNA export. Inhibiting mTOR with pathway-specific inhibitors like rapamycin, or targeting eIF4E with agents such as 4EGI-1, can disrupt the export of mRNAs related to protein synthesis and cell growth. This disruption may result in diminished pluripotency and changes in differentiation outcomes, highlighting the broader influence of the PI3K-Akt pathway on the regulation of gene expression in stem cells [46, 47].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the PI3K-Akt pathway has significant implications for embryonic stem cell (ESC) proliferation, differentiation potential, and overall cellular function. This pathway plays a crucial role in determining how ESCs respond to various internal and external signals, thereby influencing their behavior and fate [47, 48].
The PI3K-Akt pathway promotes proliferation by modulating the export of mRNAs encoding cell cycle regulators. Enhanced export of mRNAs for proteins such as cyclin D1 and CDK4 facilitates rapid cell division, which is essential for maintaining the stem cell population. By ensuring that these key regulatory mRNAs are efficiently exported and translated, the pathway supports the dynamic growth characteristic of ESCs [48, 49].
Differentiation potential is also influenced by the PI3K-Akt pathway through its control over the export of mRNAs linked to lineage-specific transcription factors. Activation of this pathway can favor the export of mRNAs critical for maintaining pluripotency, thus delaying differentiation. Conversely, targeted inhibition of the pathway may reduce the export of pluripotency-related mRNAs, promoting differentiation into specialized cell types. This selective regulation underscores the pathway's role in balancing self-renewal and differentiation in ESCs [49, 50].
In addition to proliferation and differentiation, the PI3K-Akt pathway impacts broader cellular functions, including metabolism and stress response, by regulating the export of corresponding mRNAs. In ESCs, Akt-driven export of mRNAs encoding metabolic enzymes helps meet the energetic demands of rapidly proliferating cells. By coordinating these various aspects of cellular function, the PI3K-Akt pathway ensures that ESCs can efficiently adapt to their developmental context and maintain their unique properties [47, 49].
Therapeutic and Research Implications:
The ability to modulate mRNA export through the PI3K-Akt pathway opens avenues for manipulating ESC fate for research or therapeutic purposes. By altering the export of specific mRNAs, researchers could control stem cell potency and direct differentiation into specific lineages, potentially improving outcomes in regenerative medicine and stem cell therapy [48, 50].
- MAPK/ERK Pathway
The MAPK/ERK Pathway is crucial in regulating cell growth, differentiation, and survival, and it plays an essential role in mRNA export during embryonic development. By interacting with components of the mRNA export machinery, the MAPK/ERK pathway can influence which mRNAs are exported, impacting the expression of genes involved in pluripotency and differentiation in embryonic stem cells (ESCs). This regulation is key to maintaining the balance between self-renewal and differentiation in stem cells [51, 52].
Molecular Mechanisms of MAPK/ERK in mRNA Export Regulation:
The MAPK/ERK pathway is crucial for cell signaling and is activated by various growth factors, cytokines, and mitogens. These signaling molecules bind to receptor tyrosine kinases (RTKs) on the cell surface, triggering a cascade that leads to the activation of RAS. Subsequently, RAS activates RAF, which phosphorylates and activates MEK1/2. This series of events culminates in the phosphorylation of ERK1/2 (extracellular signal-regulated kinases). Once phosphorylated, ERK1/2 translocates to the nucleus, where it interacts with several components involved in mRNA export [52, 53].
Among the key components of the MAPK/ERK pathway that influence mRNA export is ERK1/2 itself. When phosphorylated, ERK1/2 enters the nucleus and modulates mRNA export by engaging with RNA-binding proteins (RBPs) and transcription factors associated with mRNA processing. This interaction allows ERK to influence the activity of proteins involved in splicing and export, thereby affecting the export of specific mRNAs [53, 54].
SR (serine/arginine-rich) proteins are another significant target of the MAPK/ERK pathway in the context of mRNA export. These proteins are essential for both splicing and export processes. Notably, SRSF1, a well-characterized SR protein, is activated through ERK signaling and plays a crucial role in selecting mRNAs for export. This is particularly relevant for mRNAs involved in cell cycle progression and differentiation, indicating a direct link between ERK signaling and the regulation of mRNA that governs critical cellular functions [54, 55].
The TREX (Transcription Export) Complex is also impacted by ERK1/2 activation. This complex includes essential components such as THOC5 and ALYREF, which are integral to mRNA processing and export. Through phosphorylation events mediated by ERK, the function of the TREX complex is influenced, affecting the coupling of transcription with mRNA export. This regulation highlights the complex interaction between signaling pathways and mRNA export mechanisms, underlining the importance of ERK in the spatial and temporal control of gene expression [55, 56].
Interaction with mRNA Export Machinery:
The MAPK/ERK pathway plays a crucial role in regulating the mRNA export machinery through a series of phosphorylation events that modulate the function of essential proteins and complexes involved in the export process. These modifications significantly influence the efficiency and specificity of mRNA export [56, 57].
One critical aspect of this regulation is the phosphorylation of mRNA export factors. ERK1/2 can directly phosphorylate export factors such as NXF1 (Nuclear Export Factor 1), which alters its binding affinity to export-competent mRNAs. This modification has the potential to either enhance or inhibit the export of specific mRNAs, allowing the cell to respond to developmental cues and changing physiological needs [57, 58].
The TREX (Transcription Export) Complex, vital for coupling transcription with mRNA export, is also subject to regulation by ERK-mediated phosphorylation. THOC5, a key component of the TREX complex, is directly regulated by ERK signaling. This regulation influences mRNA export by modulating the binding of the TREX complex to mRNAs, particularly those involved in the differentiation of embryonic stem cells (ESCs) [58, 59].
In addition to these factors, ERK signaling can affect various RNA-binding proteins that play crucial roles in mRNA export, such as HNRNPK and SR proteins. Phosphorylation events can modify the activity of these proteins, enhancing their ability to facilitate mRNA transport through nuclear pore complexes (NPCs). This modulation ultimately impacts the export efficiency of mRNAs essential for maintaining pluripotency and driving differentiation processes. Through these interconnected mechanisms, the MAPK/ERK pathway orchestrates the spatial and temporal regulation of gene expression critical for cellular function and development [59, 60].
Role in Embryonic Stem Cell Differentiation and Potency:
The MAPK/ERK pathway is essential for maintaining the balance between embryonic stem cell (ESC) self-renewal and differentiation by regulating the export of mRNAs that encode pluripotency and lineage-specific factors. This regulatory mechanism plays a critical role in determining the fate of stem cells during development [60, 61].
In ESCs, the MAPK/ERK pathway significantly influences the export of mRNAs that encode key transcription factors, such as Oct4, Sox2, and Nanog. These factors are crucial for sustaining pluripotency, and ERK signaling has been shown to modulate both the export and expression levels of these mRNAs. By promoting the accumulation of pluripotency factors, the MAPK/ERK pathway helps maintain the undifferentiated state of stem cells [62, 63].
As ESCs begin to differentiate, the role of ERK signaling shifts to selectively enhancing the export of mRNAs that encode transcription factors promoting differentiation. For instance, Brachyury, which is essential for mesoderm formation, and Sox17, important for endoderm specification, are influenced by ERK pathway modulation. This targeted regulation allows for precise control over the export and expression levels of differentiation-promoting factors, facilitating lineage commitment in differentiating cells. Through these mechanisms, the MAPK/ERK pathway orchestrates the transition from self-renewal to differentiation, highlighting its fundamental role in stem cell biology [63, 64].
Modulation of mRNA Export and Its Effects on ESCs:
Targeted manipulation of the MAPK/ERK pathway can significantly influence mRNA export in embryonic stem cells (ESCs), thereby affecting their behavior and differentiation potential.
Inhibition of ERK activity, achieved through the use of MEK inhibitors such as U0126 or PD98059, prevents ERK activation and subsequently reduces the export of mRNAs essential for differentiation. This inhibition enhances pluripotency by blocking the export of differentiation-related mRNAs, promoting self-renewal in stem cells. As a result, the ability of ESCs to maintain an undifferentiated state is reinforced, allowing for extended periods of self-renewal [65, 66].
Conversely, promoting ERK activation increases the export of mRNAs associated with differentiation, which can expedite the differentiation process. Activation of ERK signaling has been demonstrated to enhance the export of mRNAs involved in lineage-specific commitment. This modulation promotes the transition from pluripotency to a differentiated state, facilitating the lineage specification necessary for effective development [66, 67].
ERK signaling also impacts splicing factors, influencing the selection of mRNA isoforms for export. This fine-tuning of splicing and export coupling significantly affects the repertoire of exported mRNAs, directly impacting the stem cell’s capacity to differentiate into various lineages. Through these mechanisms, targeted manipulation of the MAPK/ERK pathway emerges as a powerful strategy for controlling the differentiation of ESCs and shaping their developmental outcomes [67, 68].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the MAPK/ERK pathway significantly influences the behavior of embryonic stem cells (ESCs), affecting key cellular functions such as proliferation, differentiation, and cellular homeostasis [68].
ERK signaling plays a crucial role in promoting the export of mRNAs that regulate cell cycle progression, including cyclin D and CDK4. Enhanced ERK activity supports ESC proliferation by facilitating the export of these mRNAs. In contrast, inhibiting ERK signaling can suppress cell cycle progression, potentially leading to reduced rates of proliferation in stem cells [69, 70].
The MAPK/ERK pathway also modulates the export of mRNAs encoding lineage-specific factors, thereby influencing the differentiation potential of ESCs. For example, during neural differentiation, ERK signaling enhances the export of mRNAs that promote neurogenesis, facilitating the transition toward the neural lineage. This selective export of mRNAs is essential for guiding the differentiation process and ensuring that stem cells can adopt specific fates [51, 67].
In addition to proliferation and differentiation, the MAPK/ERK pathway regulates the export of mRNAs involved in metabolic processes and stress responses. In ESCs, ERK-driven export of mRNAs for metabolic enzymes supports the high-energy demands associated with stem cell maintenance. The export of stress-responsive mRNAs also plays a critical role in managing cellular responses to environmental changes. Through these regulatory mechanisms, the MAPK/ERK pathway maintains cellular homeostasis and ensures the proper functioning of stem cells in various contexts [52, 68].
Therapeutic and Research Implications:
The ability to manipulate mRNA export through the MAPK/ERK pathway offers potential for controlling ESC fate, with implications for regenerative medicine and therapeutic applications. By selectively influencing mRNA export, researchers can modulate stem cell potency, directing ESCs toward specific differentiation pathways or enhancing their self-renewal potential [54, 70].
- Wnt/β-catenin signaling pathway
The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development by regulating various processes, including cell proliferation, differentiation, and mRNA export. This pathway influences embryonic stem cell (ESC) differentiation and pluripotency through its effects on gene expression and mRNA export. By interacting with components of the mRNA export machinery, the Wnt/β-catenin pathway modulates the export of specific mRNAs, impacting the expression of pluripotency factors and lineage-specific genes, which is essential for directing ESC fate during development [71, 72].
Molecular Mechanisms of Wnt/β-catenin in mRNA Export Regulation:
The Wnt/β-catenin pathway is activated through the binding of Wnt ligands to Frizzled receptors and LRP5/6 co-receptors on the cell surface. This interaction leads to the stabilization and subsequent nuclear translocation of β-catenin. Within the nucleus, β-catenin engages with TCF/LEF transcription factors, which play a crucial role in regulating the expression of target genes, including those associated with mRNA export [72, 73].
Key components of the Wnt/β-catenin pathway significantly influence mRNA export. Once stabilized and translocated to the nucleus, β-catenin not only regulates transcription but also interacts with RNA-binding proteins and components of the export machinery. This interaction affects the export of mRNAs that are critical for stem cell differentiation and the maintenance of pluripotency [73, 74].
TCF/LEF transcription factors, in conjunction with β-catenin, modulate the expression of genes encoding mRNA export factors. This regulation indirectly impacts export processes in embryonic stem cells (ESCs). By controlling the transcription of export factors, TCF/LEF factors contribute to the management of the repertoire of exported mRNAs, further linking the Wnt/β-catenin pathway to the complex interaction of mRNA regulation in cellular development [74, 75].
Interaction with mRNA Export Machinery:
The Wnt/β-catenin pathway influences mRNA export by interacting with the export machinery, specifically targeting key proteins and RNA-binding proteins. β-catenin regulates the expression of Nuclear Export Factor 1 (NXF1), a primary export receptor, by activating the transcription of the NXF1 gene. NXF1 binds to mRNA and facilitates its export through the nuclear pore complex (NPC). This regulation by β-catenin determines which mRNAs are exported, thereby affecting overall gene expression [75, 76].
Additionally, β-catenin interacts with RNA-binding proteins (RBPs), such as HNRNPK and ALYREF, which serve as bridges between the export machinery and mRNA. The pathway can modulate the activity of these RBPs, particularly within the context of the TREX (Transcription Export) Complex. The TREX complex plays a crucial role in coupling mRNA processing with export, thereby enhancing the efficiency of mRNA export during transcription [76, 77].
The influence of β-catenin extends to the expression of nucleoporins, including NUP98, which are essential components of the NPC. By regulating nucleoporin expression, β-catenin helps control both the rate and specificity of mRNA export. This regulation ultimately influences the selection of mRNAs for export during embryonic stem cell differentiation, linking the Wnt/β-catenin pathway to critical processes in gene expression and cellular development [77, 78].
Role in Embryonic Stem Cell Differentiation and Potency:
The Wnt/β-catenin pathway plays a crucial role in regulating embryonic stem cell (ESC) differentiation and potency by influencing the export of mRNAs that encode factors essential for pluripotency and differentiation [78].
In ESCs, the pathway modulates the export of mRNAs encoding pluripotency factors such as Oct4, Sox2, and Nanog. Active β-catenin signaling enhances the export and expression of these mRNAs, which is vital for maintaining an undifferentiated state and supporting self-renewal. This regulation ensures that the stem cells retain their pluripotent characteristics, allowing them to respond to differentiation cues appropriately [79, 80].
During differentiation, the Wnt/β-catenin pathway promotes the export of mRNAs encoding lineage-specific transcription factors. For instance, β-catenin influences the expression and export of Brachyury, which is important for mesodermal lineage commitment, as well as GATA6, which plays a critical role in endodermal differentiation. This selective export of mRNAs is essential for timely lineage commitment and the activation of genes that drive the differentiation process, linking the pathway directly to developmental outcomes in ESCs [80, 81].
Modulation of mRNA Export and Its Effects on ESCs:
Targeted manipulation of the Wnt/β-catenin pathway has the potential to significantly alter mRNA export efficiency in embryonic stem cells (ESCs), directly influencing their behavior and developmental potential [81].
Activating the pathway using agonists such as CHIR99021, a GSK-3 inhibitor, promotes β-catenin stabilization and enhances the export of mRNAs that support pluripotency and proliferation. This activation can prolong the self-renewal phase of ESCs, delaying differentiation by reinforcing the export of pluripotency-associated mRNAs. The resulting increase in these mRNAs helps maintain an undifferentiated state, which is crucial for the cells' developmental versatility [82, 83].
Conversely, inhibition of the Wnt/β-catenin signaling pathway using compounds like XAV939, a tankyrase inhibitor, suppresses the export of mRNAs associated with pluripotency, thereby promoting differentiation. By inhibiting β-catenin signaling, the export of pluripotency-associated mRNAs is reduced while the export of mRNAs that promote differentiation is enhanced. This shift encourages ESCs to commit to specific lineages, pushing them toward differentiation [83, 84].
Modulating RNA-binding proteins (RBPs) and export factors regulated by β-catenin provides another strategy for influencing mRNA export. Researchers can manipulate which mRNAs are exported, impacting the delicate balance between self-renewal and differentiation in ESCs. This targeted approach enables controlled manipulation of ESC fate, with potential applications in developmental studies and therapeutic contexts [84, 85].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the Wnt/β-catenin pathway significantly influences various aspects of embryonic stem cell (ESC) behavior, including proliferation, differentiation, and overall cellular function [85].
Active Wnt/β-catenin signaling enhances the export of mRNAs associated with cell cycle progression, such as cyclin D1 and c-Myc. This export supports the high proliferation rate of ESCs, which is critical for maintaining adequate cell numbers during early development. The ability to efficiently export these mRNAs allows ESCs to rapidly enter the cell cycle and sustain their growth [85, 86].
The Wnt/β-catenin pathway also plays a crucial role in regulating differentiation by modulating the export of mRNAs encoding lineage-specific factors. For example, during neural differentiation, the pathway promotes the export of mRNAs that favor neurogenesis while inhibiting the export of factors that support alternative lineages. This selective regulation ensures that ESCs can commit to specific developmental pathways in a timely manner [86, 87].
In addition to proliferation and differentiation, the Wnt/β-catenin pathway impacts overall cellular function and metabolism by regulating the export of mRNAs involved in metabolic pathways. These pathways are essential for meeting the energetic demands of rapidly dividing ESCs. Through β-catenin's influence on mRNA export, ESCs can fine-tune their metabolic activities to support either a pluripotent state or a differentiating state, reflecting the dynamic nature of their cellular environment [87, 88].
Therapeutic and Research Implications:
Manipulating the Wnt/β-catenin pathway provides opportunities to control mRNA export and, consequently, ESC fate, which has implications for regenerative medicine and stem cell research. By targeting specific components within this pathway, researchers can fine-tune ESC behavior and direct differentiation into desired lineages, potentially improving stem cell-based therapeutic strategies [89, 90].
- Notch Signaling Pathway
The Notch Signaling Pathway plays a critical role in cell fate determination and differentiation during embryonic development. Known for its importance in mediating cell-cell communication, this pathway is essential for the regulation of embryonic stem cell (ESC) differentiation and maintenance of stem cell potency. Through its influence on mRNA export, the Notch pathway can modulate the expression of pluripotency factors and lineage-specific genes, which in turn affects ESC behavior and differentiation potential [91, 92].
Molecular Mechanisms of Notch Signaling in mRNA Export Regulation:
The Notch signaling pathway is initiated when a Notch receptor on one cell interacts with a ligand, such as Delta or Jagged, on an adjacent cell. Upon ligand binding, the Notch receptor undergoes proteolytic cleavages that release the Notch Intracellular Domain (NICD). The NICD subsequently translocates into the nucleus, where it interacts with the transcription factor RBPJ/CSL and other co-factors. This nuclear complex then modulates the transcription of target genes that play roles in processes such as cell differentiation and mRNA export [92, 93].
In the context of mRNA export regulation, several components of the Notch pathway are particularly relevant. The NICD can influence mRNA export by altering the expression of genes that encode export factors, thereby indirectly modulating the availability and activity of proteins involved in mRNA export. As the primary nuclear effector, RBPJ/CSL binds to NICD, functioning as a transcriptional regulator of Notch target genes. This interaction modulates the expression of components within the mRNA export machinery, impacting mRNA export dynamics in embryonic stem cells (ESCs) [93, 94].
The pathway also regulates the expression of various Notch target genes implicated in cell cycle progression, differentiation, and mRNA processing. Genes such as HES1 and HEY1 are among those influenced by Notch signaling. These genes indirectly affect the mRNA export process by regulating the expression of RNA-binding proteins and export factors, ultimately influencing cellular behavior and phenotype [94, 95].
Interaction with mRNA Export Machinery:
The Notch signaling pathway exerts influence over mRNA export by regulating crucial components of the export machinery and interacting with RNA-binding proteins. This regulatory role allows Notch to affect gene expression patterns essential for processes like ESC differentiation [95, 96].
Notch signaling modulates the transcription of NXF1 and NXF2, the primary mRNA export receptors, which influences the export of specific mRNAs during ESC differentiation. Through the regulation of NXF1/2 expression, Notch controls the selection of mRNAs that are exported, with direct implications for maintaining pluripotency and dictating lineage-specific gene expression patterns [96, 97].
Additionally, Notch signaling affects the expression and activity of RNA-binding proteins (RBPs), such as HNRNPK and SR proteins. These RBPs are critical for mRNA processing and export, playing a role in linking transcription with export. By modulating RBPs, Notch influences both the efficiency and specificity of mRNA export in ESCs, thereby impacting the overall gene expression landscape during differentiation [97, 98].
Notch signaling also affects components of the TREX (Transcription Export) Complex, including ALYREF and THOC5, as well as nucleoporins that make up the nuclear pore complex (NPC). Through the modulation of these proteins, Notch signaling dictates which mRNAs are exported, thus shaping ESC differentiation and maintaining cellular potency by selectively controlling mRNA export processes [98, 99].
Role in Embryonic Stem Cell Differentiation and Potency:
The Notch signaling pathway plays a critical role in maintaining embryonic stem cell (ESC) potency and guiding differentiation by selectively influencing the export of mRNAs associated with pluripotency and lineage-specific factors. This selective export process is essential for modulating the balance between self-renewal and differentiation in ESCs [99, 100].
In the context of pluripotency, Notch signaling can promote the export of mRNAs that encode key factors such as Oct4 and Nanog under specific conditions. By regulating the export of these pluripotency-associated mRNAs, Notch signaling helps maintain the undifferentiated state of ESCs, ensuring they retain their potential for self-renewal and the capacity to differentiate into various cell types [100, 101].
As differentiation proceeds, Notch signaling enhances the export of mRNAs encoding transcription factors that are associated with specific lineages. For example, Notch signaling is linked to the export of mRNAs like GATA2, which plays a role in hematopoiesis, and Sox9, which is associated with chondrogenesis. Through this targeted export of lineage-specific mRNAs, the Notch pathway facilitates the transition from a pluripotent state to committed lineages, promoting the development of specialized cell types [101, 102].
Modulation of mRNA Export and Its Effects on ESCs:
Manipulating the Notch signaling pathway can significantly influence mRNA export dynamics, thereby affecting the behavior of embryonic stem cells (ESCs), including their proliferation and differentiation potential. The ability to modulate Notch signaling provides a means to alter the export profiles of specific mRNAs, with implications for ESC fate decisions [102, 103].
Activation of Notch signaling, through ligands such as DLL4, can enhance the export of mRNAs that favor differentiation while reducing the export of those that support pluripotency. This shift in mRNA export profiles drives lineage-specific commitment, promoting the differentiation of ESCs into specialized cell types [103, 104].
Conversely, inhibition of Notch signaling, using agents like DAPT—a γ-secretase inhibitor—blocks Notch receptor cleavage, preventing the formation and nuclear translocation of the Notch Intracellular Domain (NICD). This inhibition reduces the export of differentiation-related mRNAs while promoting the nuclear retention of pluripotency-associated mRNAs. By doing so, Notch inhibition supports ESC self-renewal and helps maintain the undifferentiated state [104, 105].
Additionally, Notch signaling modulates the expression and activity of RNA-binding proteins (RBPs) and components of the TREX complex, which play crucial roles in mRNA export. This modulation influences the efficiency and specificity of mRNA export, affecting which mRNAs are selected for export. Consequently, these changes impact both the differentiation potential and the maintenance of pluripotency in ESCs, underscoring the importance of Notch in fine-tuning mRNA export processes [105, 106].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the Notch signaling pathway affects various aspects of embryonic stem cell (ESC) behavior, including proliferation, differentiation potential, and overall cellular function. This modulation by Notch is crucial for directing ESC fate and maintaining cellular homeostasis [106, 107].
In terms of proliferation, Notch signaling controls the export of mRNAs for key cell cycle regulators such as cyclin D1 and p21. Active Notch signaling enhances ESC proliferation by promoting the export of mRNAs that drive cell cycle progression. Conversely, when Notch signaling is inhibited, the export of these mRNAs is reduced, leading to a decrease in proliferation rates, which impacts ESC growth dynamics [107, 108].
The Notch pathway also plays a crucial role in determining differentiation outcomes by influencing the export of mRNAs associated with specific lineages. Activation of Notch signaling facilitates differentiation toward various cell types by promoting the export of lineage-specific factors. For instance, Notch can promote neurogenesis by facilitating the export of neurogenic mRNAs. Depending on the cellular context, Notch activation can also influence differentiation toward hematopoietic or endothelial lineages, demonstrating its diverse role in lineage specification [108, 109].
In addition to proliferation and differentiation, Notch signaling impacts cellular function and homeostasis by regulating the export of mRNAs involved in metabolic processes and stress responses. This selective export helps maintain a balanced cellular environment, either supporting ESC maintenance or preparing cells for differentiation. By fine-tuning the export of these mRNAs, Notch signaling contributes to the broader regulation of ESC functionality, ensuring that cells can respond to changing conditions and developmental cues effectively [109, 110].
Therapeutic and Research Implications:
The ability to manipulate Notch signaling provides opportunities to control mRNA export and ESC fate. This has implications for regenerative medicine, as targeted modulation of Notch can direct ESC differentiation into specific lineages or maintain stem cell potency for extended periods, enhancing the utility of ESCs in therapeutic applications [109, 110].
- TGF-β (Transforming Growth Factor-beta) signaling pathway
The TGF-β (Transforming Growth Factor-beta) signaling pathway is integral to embryonic development, regulating cellular processes like proliferation, differentiation, and gene expression. In the context of embryonic stem cells (ESCs), TGF-β signaling modulates mRNA export, impacting pluripotency and differentiation. By interacting with the mRNA export machinery, TGF-β signaling influences the export of specific mRNAs that are critical for maintaining stem cell potency or promoting differentiation [110, 111].
Molecular Mechanisms of TGF-β Signaling in mRNA Export Regulation:
The TGF-β pathway initiates upon binding of TGF-β ligands to type I and type II serine/threonine kinase receptors. This interaction triggers a cascade of events, leading to the phosphorylation and subsequent activation of Smad proteins, particularly Smad2 and Smad3. Once activated, Smad2 and Smad3 form complexes with Smad4, which then translocate to the nucleus to regulate the transcription of TGF-β-responsive genes. These genes include those involved in the regulation of mRNA export, highlighting the TGF-β pathway’s influence on this essential cellular process [111, 112].
Within the context of mRNA export, Smad complexes (Smad2/3 and Smad4) play a critical role by interacting with transcription factors and co-activators in the nucleus. Through these interactions, Smad complexes modulate the expression of export factors and RNA-binding proteins, thereby influencing the export of specific mRNAs. The regulatory capacity of these complexes underscores their importance in the control of mRNA export, linking TGF-β signaling to broader cellular functions [112, 113].
TGF-β receptors, TGFBR1 and TGFBR2, are also pivotal to this regulatory mechanism. Beyond their role in Smad activation, these receptors can trigger Smad-independent pathways that further contribute to mRNA export regulation. For example, TGF-β signaling can activate non-Smad pathways such as PI3K/Akt and MAPK. These pathways may influence mRNA export indirectly by modifying components of the export machinery, thus expanding the scope of TGF-β signaling in the regulation of gene expression [113, 114].
Interaction with mRNA Export Machinery:
The TGF-β pathway influences mRNA export by modulating the expression and activity of key export factors and RNA-binding proteins (RBPs) that interact with the mRNA export machinery. Through these regulatory actions, TGF-β signaling exerts control over which mRNAs are exported, impacting cell differentiation and maintaining the balance between pluripotency and lineage commitment [114, 115].
One of the critical factors affected by TGF-β signaling is Nuclear Export Factor 1 (NXF1). NXF1 acts as an essential export receptor that facilitates mRNA transit through the nuclear pore complex (NPC). By modulating NXF1 expression, TGF-β influences the export of specific mRNAs, thereby playing a direct role in determining the gene expression profile that governs stem cell states and differentiation processes [116, 117].
The TREX complex, a pivotal component in coupling transcription to mRNA export, is also regulated by TGF-β signaling. This complex includes proteins such as ALYREF and THOC5, which are crucial for the selective export of mRNAs during differentiation. TGF-β signaling can influence the expression of TREX components, suggesting a mechanism by which the pathway directs the export of mRNAs linked to specific differentiation outcomes [117, 118].
TGF-β signaling further regulates RNA-binding proteins (RBPs) such as HNRNPK, SERBP1, and YBX1. These RBPs are involved in multiple aspects of mRNA processing, stability, and export. By modulating the activity of these proteins, TGF-β signaling contributes to the selective export of mRNAs, thereby impacting gene expression profiles during embryonic stem cell differentiation. This regulation highlights TGF-β’s broader role in orchestrating the cellular machinery that governs mRNA export and gene expression [118, 119].
Role in Embryonic Stem Cell Differentiation and Potency:
TGF-β signaling plays a crucial role in embryonic stem cell (ESC) differentiation and potency by regulating the export of mRNAs that encode key pluripotency factors and differentiation markers. Through this mechanism, TGF-β influences the balance between ESC self-renewal and lineage commitment, thereby shaping cell fate [119, 120].
In ESCs, TGF-β signaling modulates the export of mRNAs encoding pluripotency factors such as Nanog, Oct4, and Sox2. The export of these mRNAs is regulated based on the differentiation stage, allowing TGF-β to either promote or inhibit their expression as needed. This selective control enables TGF-β to adjust the self-renewal capacity and maintain the pluripotent state of ESCs in response to developmental cues [120, 121].
TGF-β signaling also directs ESC differentiation into specific lineages, including mesoderm and endoderm. By enhancing the export of mRNAs that encode lineage-specific factors, TGF-β ensures the appropriate expression of genes necessary for differentiation. For instance, the pathway regulates the export of Brachyury mRNA to drive mesodermal differentiation and GATA6 mRNA for endodermal lineage specification. This selective export mechanism orchestrates the expression of lineage-determining genes, facilitating the orderly progression of ESC differentiation into specialized cell types [121, 122].
Modulation of mRNA Export and Its Effects on ESCs:
The targeted manipulation of TGF-β signaling can influence mRNA export efficiency, thereby affecting embryonic stem cell (ESC) behavior, including proliferation, differentiation potential, and cellular function. By adjusting TGF-β activity, it is possible to direct the fate of ESCs in a controlled manner, which has significant implications for developmental biology and regenerative medicine [122, 123].
Activation of TGF-β signaling, either by natural ligands or recombinant TGF-β1 protein, can promote mRNA export associated with differentiation. This activation facilitates the export of mRNAs that drive differentiation, while repressing those tied to pluripotency. Such selective export helps to shift ESCs from a pluripotent state to specific lineages by promoting the expression of differentiation-associated genes [123, 124].
Inhibiting TGF-β signaling through compounds like SB431542, a TGF-β receptor inhibitor, reduces the export of mRNAs linked to differentiation. At the same time, it maintains the export of pluripotency-associated mRNAs, helping to sustain self-renewal and preserve the pluripotent state. This approach provides a way to regulate ESC fate, making it valuable for developmental studies where controlled maintenance of pluripotency is required [124, 125].
Through Smad-dependent transcriptional regulation, TGF-β signaling also modulates the expression of export machinery components such as NXF1 and nucleoporins. By altering these components, TGF-β can affect the export efficiency of specific mRNAs, which, in turn, impacts ESC differentiation and function. This modulation illustrates the pathway’s capacity to fine-tune cellular responses by regulating mRNA export dynamics [125, 126].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the TGF-β pathway plays a significant role in embryonic stem cell (ESC) proliferation, differentiation, and overall function, directly impacting their developmental potential and adaptability [126].
TGF-β signaling influences ESC proliferation by modulating the export of cell cycle-related mRNAs, such as cyclin D1 and p21. While TGF-β activation often suppresses proliferation in differentiated cells, it can sustain ESC proliferation under specific conditions by selectively exporting mRNAs critical for cell cycle progression. This regulatory flexibility allows TGF-β to adapt its effects based on the cellular context, maintaining proliferation where needed to support ESC self-renewal [126, 127].
The pathway also impacts differentiation potential by promoting the export of mRNAs that drive lineage specification. In ESCs, TGF-β signaling enhances mesoderm and endoderm differentiation by selectively exporting lineage-specific mRNAs, such as Sox17 and Mixl1. This selective export mechanism is crucial for ESCs to commit to specific developmental pathways, facilitating the proper progression from pluripotency to specialized cell types [127, 128].
TGF-β signaling further supports ESC function and homeostasis by regulating the export of mRNAs involved in stress response, metabolism, and other key pathways. This export regulation enables ESCs to adapt to varying developmental cues and environmental changes, ensuring they can respond dynamically during differentiation. Through these processes, TGF-β signaling contributes to the maintenance of cellular homeostasis and functional integrity in ESCs [128, 129].
Therapeutic and Research Implications:
Manipulating TGF-β signaling offers a valuable approach to control mRNA export and ESC fate, which can aid in regenerative medicine and developmental studies. For instance, selectively activating or inhibiting TGF-β can steer ESC differentiation into desired lineages, which is beneficial for tissue engineering and cell therapy. Additionally, understanding how TGF-β modulates mRNA export can inform strategies for managing diseases associated with dysregulated stem cell differentiation or abnormal TGF-β signaling [129, 130].
- mTOR (mechanistic Target of Rapamycin) signaling pathway
The mTOR (mechanistic Target of Rapamycin) signaling pathway is central to regulating cellular growth, proliferation, and differentiation, particularly during embryonic development. This pathway plays a crucial role in modulating mRNA export by coordinating nutrient sensing and cellular energy status with gene expression. In embryonic stem cells (ESCs), mTOR signaling influences pluripotency and differentiation by regulating the export of mRNAs associated with these processes [131, 132].
Molecular Mechanisms of mTOR Signaling in mRNA Export Regulation:
The mTOR pathway plays a crucial role in cellular signaling, responding to various stimuli such as growth factors, amino acids, and cellular energy levels. This pathway is primarily mediated by two distinct complexes: mTORC1 and mTORC2, each contributing to different cellular processes, including the regulation of mRNA export [132, 133].
mTORC1 is sensitive to nutrient and energy levels, functioning as a central regulator of protein synthesis and autophagy. It phosphorylates a variety of substrates that are integral to these processes. One of the key roles of mTORC1 involves the regulation of specific mRNAs, which it achieves by controlling the availability and activity of RNA-binding proteins (RBPs) and export factors. This regulation is vital for maintaining proper gene expression and ensuring that the necessary proteins are synthesized in response to cellular needs [133, 134].
In contrast, mTORC2 is primarily activated by growth factors and is known for its influence on the actin cytoskeleton and overall cellular metabolism. While its connection to mRNA export is less direct than that of mTORC1, mTORC2 can still impact the export process. It achieves this by modulating cytoskeletal components, which are crucial for nucleocytoplasmic transport. This interplay highlights the complex regulatory network in which mTORC1 and mTORC2 operate, ensuring that cellular functions are finely tuned to external and internal cues [134, 135].
Interaction with mRNA Export Machinery:
mTOR signaling plays a critical role in the regulation of mRNA export by modulating key export factors and RNA-binding proteins (RBPs) that are essential for mRNA processing and transit through the nuclear pore complex (NPC). This complex regulation ensures that mRNAs are properly exported from the nucleus to the cytoplasm, facilitating effective gene expression [135, 136].
Eukaryotic Initiation Factor 4E (eIF4E) is one of the significant proteins influenced by mTORC1 signaling. In addition to its primary role in translation initiation, eIF4E is also involved in nuclear mRNA export. The phosphorylation of 4E-BP1 by mTORC1 enhances the activity of eIF4E by releasing it from inhibitory complexes. Once freed, eIF4E can bind to NXF1, an mRNA export receptor, thus facilitating the export of mRNA from the nucleus [136, 137].
S6 Kinase (S6K) is another important player in mTORC1 signaling. Activated by mTORC1, S6K phosphorylates several RBPs critical for mRNA export, including HNRNPA1 and SR proteins. These RBPs are not only vital for mRNA splicing but also influence the selection and dynamics of mRNA export. The phosphorylation state of these proteins can significantly affect the efficiency and specificity of mRNA export [137, 138].
The Transcription Export Complex (TREX) also plays a crucial role in mRNA export, and its components are influenced by mTOR signaling. Key proteins within the TREX complex, such as ALYREF and THOC5, are essential for efficient mRNA export, particularly during embryonic stem cell differentiation. mTOR can modulate the activity of these TREX components through both direct phosphorylation and indirect signaling pathways, underscoring the complexity of mRNA export regulation in response to cellular conditions [139, 140].
Role in Embryonic Stem Cell Differentiation and Potency:
The mTOR pathway is integral to the differentiation of embryonic stem cells (ESCs) and the maintenance of their pluripotency by selectively regulating mRNA export. This regulation is crucial for ensuring the appropriate expression of both pluripotency factors and differentiation markers, allowing for precise control over cell fate decisions [140, 141].
mTOR signaling plays a crucial role in promoting the export of mRNAs that encode pluripotency factors, such as Nanog and Oct4. These factors are essential for maintaining the self-renewal capabilities of ESCs. The pathway’s influence on export machinery enables ESCs to retain these pluripotency-associated mRNAs when mTOR signaling is active, thereby supporting their undifferentiated state [141, 142].
As ESCs begin to differentiate into various lineages, mTOR signaling facilitates this process by enhancing the export of mRNAs encoding differentiation factors. For instance, during early differentiation, the activation of mTORC1 promotes the export of mRNAs that encode transcription factors like GATA4 and Sox17. These factors are critical for the differentiation of ESCs into the mesoderm and endoderm lineages, respectively. Through this regulatory mechanism, mTOR signaling ensures that the transition from pluripotency to specific cell fates is tightly controlled [142, 143].
Modulation of mRNA Export and Its Effects on ESCs:
Targeted manipulation of the mTOR pathway can significantly alter mRNA export dynamics in embryonic stem cells (ESCs), thereby impacting their proliferation, differentiation potential, and overall cellular function. This pathway serves as a critical regulatory mechanism that influences how ESCs respond to various internal and external signals [143, 144].
Activation of mTOR signaling through growth factors or nutrient availability enhances mRNA export related to differentiation and growth processes. The activation of mTORC1 promotes the export of mRNAs encoding proteins involved in cell cycle progression, such as cyclin D1 and c-Myc. This increased export enhances both the proliferation and differentiation of ESCs, facilitating their transition to specialized cell types [144, 145].
In contrast, the inhibition of mTOR signaling, using compounds such as rapamycin, leads to a reduction in mRNA export associated with differentiation. In this context, pluripotency-associated mRNAs are retained within the nucleus, which supports the maintenance of ESC self-renewal. Treatment with rapamycin can also diminish the export of differentiation markers, making it an effective tool for sustaining ESC pluripotency in culture conditions [145, 146].
Additionally, mTOR signaling has been shown to influence the expression and function of nucleoporins, which are integral components of the nuclear pore complex (NPC). By modulating nucleoporins such as Nup98 and Nup153, mTOR can impact the efficiency of mRNA export, thereby altering the delicate balance between pluripotency and differentiation. This regulatory interplay underscores the importance of mTOR in maintaining ESC characteristics and guiding their fate decisions [146, 147].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
mTOR-mediated regulation of mRNA export significantly impacts the behavior of embryonic stem cells (ESCs), influencing key aspects such as proliferation, differentiation, and cellular homeostasis. This regulatory mechanism is crucial for ensuring that ESCs respond appropriately to various signaling cues [147, 148].
By promoting the export of mRNAs that govern cell growth and cell cycle progression, mTOR enhances ESC proliferation. For instance, active mTOR signaling increases the export of mRNAs such as cyclin D1 and cyclin E. This enhancement drives cells through the cell cycle, facilitating their growth and self-renewal [148, 149].
The differentiation potential of ESCs is also regulated by mTOR signaling through the modulation of lineage-specific mRNA export. Activation of the mTOR pathway can enhance the differentiation of ESCs into specific lineages, such as mesodermal and endodermal fates, by promoting the export of mRNAs associated with these developmental pathways. This targeted export is essential for the precise differentiation of ESCs into functional cell types [149, 150].
In addition to proliferation and differentiation, mTOR signaling plays a critical role in maintaining cellular homeostasis. The pathway influences the export of mRNAs involved in metabolism and stress response mechanisms, which are vital for sustaining ESC homeostasis during differentiation. By ensuring the selective export of mRNAs related to oxidative phosphorylation and autophagy, mTOR supports cellular adaptation during lineage commitment, enabling ESCs to navigate the challenges associated with differentiation [148, 149].
Therapeutic and Research Implications:
The ability to manipulate mTOR signaling provides valuable opportunities for directing ESC fate in both research and therapeutic applications. For instance, targeted inhibition of mTOR can maintain ESC pluripotency, while its activation can promote differentiation toward specific lineages. This manipulation of mRNA export dynamics via mTOR signaling is essential for applications in tissue engineering, where controlling ESC differentiation is necessary [147, 150].
- p53 signaling pathway
The p53 signaling pathway is a crucial regulator of cellular responses to stress, including DNA damage, oxidative stress, and oncogenic signals. It plays a significant role in embryonic development by influencing cell cycle control, apoptosis, and differentiation. Recent research has highlighted the importance of the p53 pathway in regulating mRNA export, particularly in embryonic stem cells (ESCs). Understanding how p53 interacts with the mRNA export machinery can provide insights into the regulation of pluripotency and differentiation during development [151, 152].
Molecular Mechanisms of p53 Signaling in mRNA Export Regulation:
The p53 pathway is activated in response to various stressors, initiating the transcription of target genes that are integral to processes such as cell cycle arrest, apoptosis, and DNA repair. Upon activation, p53 plays a crucial role in influencing mRNA export through multiple mechanisms [152, 153].
One significant mechanism is transcriptional activation, wherein p53 regulates the expression of genes that are essential for mRNA export and processing. This includes mRNA export factors and RNA-binding proteins (RBPs). Key targets of p53 encompass proteins that facilitate nucleocytoplasmic transport, which is vital for the effective export of mRNA from the nucleus to the cytoplasm [153, 154].
In addition to transcriptional activation, p53 is subject to various post-translational modifications, including phosphorylation and acetylation. These modifications can significantly alter p53's activity and its interactions with downstream targets. Furthermore, such modifications can influence p53's interactions with components of the mRNA export machinery, thereby affecting its regulatory role in the export process [154, 155].
Interaction with mRNA Export Machinery:
The p53 pathway interacts with the mRNA export machinery through various proteins and complexes that facilitate the transport of mRNA from the nucleus to the cytoplasm. One key component in this process is the Nuclear Export Factor 1 (NXF1), which is essential for the export of the majority of mRNAs. Studies have shown that p53 can modulate the expression and activity of NXF1, thereby impacting the overall efficiency of mRNA export. By enhancing NXF1 levels, p53 facilitates the export of specific mRNAs, thereby playing a crucial role in gene expression regulation [155, 156].
In addition to export factors, p53 also influences RNA-binding proteins (RBPs) that are vital for mRNA stability and export. Proteins such as HNRNPK and YBX1 are regulated by p53 and are involved in mRNA processing and stability. The interaction of these RBPs with the p53 pathway can significantly affect which mRNAs are exported, particularly during embryonic stem cell differentiation [156, 157].
The p53 signaling pathway also impacts components of the Transcription Export Complex (TREX), which is critical for coupling transcription with export. By regulating the expression of proteins such as ALYREF and THOC5, p53 enhances the efficiency of mRNA export. This complex regulation underscores the importance of p53 in orchestrating the interplay between transcription and mRNA export, contributing to the overall dynamics of gene expression [157, 158].
Role in Embryonic Stem Cell Differentiation and Potency:
The p53 signaling pathway significantly impacts embryonic stem cell (ESC) differentiation and the maintenance of pluripotency through its regulation of mRNA export. p53 influences the export of mRNAs encoding essential pluripotency factors such as Oct4, Sox2, and Nanog. By modulating the export of these critical mRNAs, p53 plays a vital role in sustaining the pluripotent state of ESCs. In conditions of cellular stress, p53 may reduce the export of pluripotency-associated mRNAs, thereby promoting differentiation [158, 159].
In addition to its role in maintaining pluripotency, p53 signaling also facilitates the differentiation of ESCs into specific lineages. This is achieved by regulating the export of mRNAs that encode lineage-specific factors. During differentiation, p53 can enhance the export of mRNAs associated with mesodermal or endodermal lineage commitment, thus driving the process of lineage specification. This regulatory mechanism underscores the dual role of p53 in both maintaining pluripotency and promoting differentiation in embryonic stem cells [159, 160].
Modulation of mRNA Export and Its Effects on ESCs:
Targeted manipulation of the p53 signaling pathway can significantly alter mRNA export efficiency in embryonic stem cells (ESCs), impacting their proliferation, differentiation potential, and overall cellular function. Activating p53 through stressors such as DNA damage or hypoxia leads to increased levels of p53 and its target genes. This activation promotes the export of specific differentiation-related mRNAs while inhibiting pluripotency-associated mRNAs, thereby facilitating the processes of differentiation [160, 161].
In contrast, inhibiting p53 signaling through the use of inhibitors or genetic knockdown approaches maintains higher levels of pluripotency-associated mRNAs within the nucleus. This reduction in p53 activity may prevent differentiation, allowing ESCs to remain in a proliferative and undifferentiated state [161, 162].
Changes in p53 activity also affect the expression and function of mRNA export factors, including NXF1 and nucleoporins. By regulating the components of the export machinery, p53 can influence the overall efficiency of mRNA export, thereby affecting the balance between maintaining pluripotency and promoting differentiation in ESCs. This complex interplay highlights the critical role of p53 in determining the fate of these cells [162, 163].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the p53 pathway has a significant impact on the behavior of embryonic stem cells (ESCs). Activation of p53 often leads to cell cycle arrest in response to stress signals. This mechanism modulates the export of mRNAs that regulate cell cycle progression, such as p21, thereby influencing ESC proliferation. While p53 typically inhibits proliferation under stress conditions, it can also promote the self-renewal of undifferentiated ESCs in the absence of stress [163, 164].
The balance between the export of pluripotency factors and differentiation-related genes is critical for determining ESC differentiation potential. p53’s role in regulating this balance facilitates a controlled response to developmental cues, which is essential for appropriate lineage specification during differentiation [165, 166].
In addition to its roles in proliferation and differentiation, p53 is crucial for maintaining overall cellular function and homeostasis. It ensures genomic stability and prevents the accumulation of mutations by regulating mRNA export. Through this regulation, p53 helps to maintain the proper expression of genes involved in stress responses and DNA repair, thereby supporting cellular homeostasis throughout differentiation and development [167, 168].
Therapeutic and Research Implications:
Manipulating the p53 signaling pathway offers potential therapeutic avenues for controlling ESC fate. For example, targeting p53 could enhance the maintenance of pluripotency or promote specific differentiation pathways. Understanding the role of p53 in mRNA export regulation may provide insights into developing strategies for tissue engineering, regenerative medicine, and cancer therapy, where the balance between cell proliferation and differentiation is crucial [169, 170].
- cAMP/PKA (cyclic adenosine monophosphate/protein kinase A)
The cAMP/PKA (cyclic adenosine monophosphate/protein kinase A) signaling pathway is a crucial regulatory mechanism in various biological processes, including embryonic development, cell proliferation, and differentiation. Recent studies have revealed its significant role in modulating mRNA export, particularly in embryonic stem cells (ESCs). Understanding the molecular mechanisms by which the cAMP/PKA pathway interacts with the mRNA export machinery can provide valuable insights into the regulation of pluripotency and differentiation during development [171, 172].
Molecular Mechanisms of the cAMP/PKA Pathway in mRNA Export Regulation:
The cAMP/PKA pathway plays a critical role in cellular signaling and is activated by various extracellular signals, including hormones and growth factors. Central to this pathway is the production of cyclic adenosine monophosphate (cAMP), which serves as a second messenger. The elevation of cAMP levels activates protein kinase A (PKA), initiating a cascade of phosphorylation events that modulate cellular responses [172, 173].
The production of cAMP is triggered by the binding of ligands such as glucagon or epinephrine to their respective receptors. This interaction activates adenylate cyclase, leading to a significant increase in intracellular cAMP levels. Elevated cAMP binds to the regulatory subunits of PKA, causing a conformational change that results in the release of its catalytic subunits [174, 175].
Once activated, PKA phosphorylates a diverse range of substrates, including transcription factors, enzymes, and cytoskeletal proteins. This phosphorylation event plays a crucial role in regulating gene expression and influencing protein interactions that are crucial for mRNA export, thereby impacting various cellular processes and responses [175, 176].
Interaction with mRNA Export Machinery:
The cAMP/PKA pathway engages with the mRNA export machinery through several key proteins, including RNA-binding proteins (RBPs) and export factors. The nuclear export of mRNA is primarily facilitated by nuclear export receptors such as NXF1 and NXT1. Evidence suggests that PKA can phosphorylate these export factors, enhancing their activity and promoting the export of specific mRNAs. For instance, phosphorylation of NXF1 increases its affinity for mRNA, thereby facilitating a more efficient export process from the nucleus [176, 177].
In addition to export factors, PKA plays a significant role in regulating various RBPs that are crucial for mRNA processing and stability. HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1) is one such RBP that can be phosphorylated by PKA, leading to changes in its binding affinity for target mRNAs and influencing their subsequent export. PKA also modulates the activity of SR proteins, which are vital for both splicing and the export of mRNAs [177, 178].
The cAMP/PKA pathway further impacts the splicing process, a critical step in mRNA maturation prior to export. Phosphorylation of splicing factors by PKA can modify their activity, thus affecting the efficiency with which mRNAs are exported from the nucleus. Collectively, these interactions highlight the integral role of the cAMP/PKA signaling pathway in coordinating mRNA export through phosphorylation events that affect both export factors and splicing mechanisms [178, 179].
Role in Embryonic Stem Cell Differentiation and Potency:
The cAMP/PKA pathway is crucial for regulating embryonic stem cell (ESC) differentiation and maintaining pluripotency, primarily through its effects on mRNA export. This pathway modulates the export of mRNAs that encode key pluripotency factors, including Oct4, Sox2, and Nanog. By controlling the export of these essential factors, the cAMP/PKA pathway contributes to the preservation of the undifferentiated state of ESCs, ensuring their capacity for self-renewal and pluripotency [179, 180].
As ESCs begin to differentiate, the cAMP/PKA pathway shifts its role by promoting the export of mRNAs that encode differentiation-associated proteins. Signaling through this pathway enhances the export of mRNAs linked to specific cell lineages, thereby facilitating the commitment of ESCs to differentiation. This dynamic regulation underscores the importance of the cAMP/PKA pathway in transitioning ESCs from a pluripotent state to a differentiated phenotype, highlighting its dual role in both maintaining pluripotency and promoting differentiation when appropriate [180, 181].
Modulation of mRNA Export and Its Effects on ESCs:
Targeted manipulation of the cAMP/PKA pathway significantly impacts mRNA export efficiency in embryonic stem cells (ESCs), influencing their proliferation, differentiation potential, and overall cellular function. Elevating cAMP levels or directly activating PKA enhances mRNA export by promoting the phosphorylation of export factors and RNA-binding proteins (RBPs). This activation results in increased export of lineage-specific mRNAs, thereby facilitating differentiation processes [181, 182].
Inhibition of the cAMP/PKA pathway yields contrasting effects. By reducing cAMP production or inhibiting PKA activity, higher levels of pluripotency-associated mRNAs remain sequestered in the nucleus, effectively preventing differentiation. Specific inhibitors of PKA can be employed to maintain this state, ensuring the retention of pluripotency in ESCs. This dual approach to manipulating the cAMP/PKA pathway demonstrates its critical role in determining the balance between pluripotency and differentiation in stem cell biology [182, 183].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the cAMP/PKA pathway significantly influences the behavior of embryonic stem cells (ESCs). Activation of this pathway promotes cell cycle progression and proliferation by enhancing the export of mRNAs associated with growth signaling. For instance, PKA signaling can increase the export of cyclins, which are essential for advancing the cell cycle [183, 184].
Modulating mRNA export through the cAMP/PKA pathway also allows for the fine-tuning of differentiation potential. The activation state of this pathway determines whether ESCs maintain their pluripotent status or commit to specific differentiation pathways. This dynamic regulation is crucial for directing the cellular fate of ESCs [184, 185, 188].
Beyond its roles in proliferation and differentiation, the cAMP/PKA pathway affects various cellular functions necessary for maintaining ESC homeostasis and functionality. It influences metabolic pathways, stress responses, and signaling cascades, highlighting its importance in orchestrating the complex behavior of ESCs in growth and development [185, 186, 187].
Therapeutic and Research Implications:
Understanding the cAMP/PKA pathway's role in regulating mRNA export opens avenues for therapeutic interventions in regenerative medicine and stem cell therapy. Manipulating this pathway could enhance the efficiency of generating specific cell types from ESCs for therapeutic purposes [189, 190].
- c-Jun N-terminal Kinase (JNK) pathway
The c-Jun N-terminal Kinase (JNK) pathway, a part of the mitogen-activated protein kinase (MAPK) signaling cascade, is integral to various cellular processes, including stress responses, apoptosis, and differentiation. Recent studies have shed light on its crucial role in regulating mRNA export, particularly during embryonic development. Understanding the molecular mechanisms by which the JNK pathway interacts with the mRNA export machinery can provide insights into the regulation of pluripotency and differentiation in embryonic stem cells (ESCs) [191, 192].
Molecular Mechanisms of the JNK Pathway in mRNA Export Regulation:
The JNK pathway is activated by various extracellular signals, including cytokines, growth factors, and environmental stressors. Upon activation, JNK phosphorylates a diverse array of substrate proteins, which can significantly impact gene expression, cytoskeletal dynamics, and the processes of mRNA processing and export. This complex regulation underscores the importance of JNK in cellular responses to external stimuli [192, 193].
JNK activation occurs through a cascade involving MAPK kinases (MKKs), particularly MKK4 and MKK7. The phosphorylation of JNK as a result of this cascade enables its translocation to the nucleus, where it can phosphorylate transcription factors such as c-Jun. This modification leads to changes in gene expression, illustrating the crucial role of JNK in linking extracellular signals to nuclear responses [193, 194].
In addition to its effects on gene expression, activated JNK also plays a critical role in mRNA export. It achieves this by modulating the activity of various proteins and export factors that are integral to the mRNA export machinery. Through these interactions, JNK influences the efficiency and regulation of mRNA transport, thereby affecting the overall gene expression landscape within the cell [195, 196].
Interaction with mRNA Export Machinery:
The JNK pathway interacts with the mRNA export machinery through a network of key proteins, including RNA-binding proteins (RBPs) and export factors. JNK phosphorylates essential nuclear export factors, such as NXF1 (nuclear export factor 1), which plays a critical role in the export of most mRNAs. This phosphorylation can enhance the binding affinity of NXF1 to mRNA, thereby facilitating the export process [196, 197].
In addition to export factors, JNK signaling also influences the activity of various RBPs, which are vital for mRNA processing, stability, and export. The phosphorylation of RBPs, such as HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), can alter their binding to target mRNAs, thereby modulating the efficiency of mRNA export [197, 198].
The Transcription and Export (TREX) complex further underscores the connection between transcription and mRNA export. JNK may modulate components of this complex, including THOC5 and ALYREF, enhancing the overall export process. These interactions highlight the integral role of the JNK pathway in regulating mRNA export and its broader implications for gene expression [198, 199].
Role in Embryonic Stem Cell Differentiation and Potency:
The JNK pathway plays a crucial role in the differentiation of embryonic stem cells (ESCs) while also maintaining their pluripotency through its regulation of mRNA export. This pathway can modulate the export of mRNAs that encode essential pluripotency factors, including Oct4, Sox2, and Nanog. Activation of JNK signaling may result in the downregulation of mRNA export for these factors, thereby promoting differentiation and diminishing the stem cell state [199, 200].
In addition to its role in pluripotency maintenance, JNK signaling has been associated with lineage-specific differentiation. During the differentiation process, JNK may enhance the export of mRNAs that are critical for specific lineage commitment. This modulation of mRNA export facilitates the transition from pluripotency to a differentiated state, highlighting the intricate balance the JNK pathway maintains in regulating stem cell fate [200, 201].
Modulation of mRNA Export and Its Effects on ESCs:
Targeted manipulation of the JNK pathway has a significant impact on mRNA export efficiency in embryonic stem cells (ESCs), which in turn affects their proliferation, differentiation potential, and overall cellular function. Activating the JNK pathway enhances the export of mRNAs associated with differentiation while inhibiting the export of pluripotency-related mRNAs. This shift promotes differentiation and alters the expression of lineage-specific genes, driving the transition of ESCs from a pluripotent to a differentiated state [201, 202].
Inhibition of the JNK pathway yields a different outcome, maintaining higher levels of pluripotency-associated mRNAs in the nucleus. This retention allows ESCs to preserve their undifferentiated state. Strategies for inhibiting JNK signaling include the use of pharmacological inhibitors and RNA interference targeting JNK. These approaches can effectively modulate the balance between differentiation and pluripotency, highlighting the critical role of the JNK pathway in regulating stem cell behavior [202, 203].
Impact on Cell Behavior: Proliferation, Differentiation Potential, and Function:
The regulation of mRNA export by the JNK pathway has significant implications for the behavior of embryonic stem cells (ESCs). JNK signaling is closely associated with cell cycle regulation. Activation of JNK can induce cell cycle arrest in response to stress, while under certain conditions, it can also support cell proliferation. The balance of JNK activity is crucial in determining how ESCs respond to growth signals, influencing their overall growth and maintenance [203, 204].
The JNK pathway is instrumental in determining the fate of ESCs. Through its modulation of mRNA export, JNK affects the equilibrium between maintaining pluripotency and committing to differentiation pathways. This regulation is vital for guiding ESCs through the transition from an undifferentiated state to specialized cell types [204, 205].
In addition to its roles in proliferation and differentiation, JNK signaling contributes to cellular homeostasis. It influences stress responses and apoptosis, ensuring that ESCs can adapt to changing conditions. By regulating mRNA export, JNK plays a crucial role in the proper expression of genes involved in these processes, which is essential for the overall function and viability of ESCs [205, 206].
Therapeutic and Research Implications:
Understanding the JNK pathway's role in regulating mRNA export offers potential therapeutic avenues for manipulating ESC fate in regenerative medicine and cancer therapy. For example, targeting the JNK pathway could enhance the efficiency of generating specific cell types from ESCs or could be used to control the differentiation of cancer stem cells [207, 208].