Tanc2-dependent direct and regulated mTOR inhibition balances mTORC1/2 signaling in developing mouse and human neurons

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Tanc2-dependent direct and regulated mTOR inhibition balances mTORC1/2 signaling in developing mouse and human neurons

https://doi.org/10.21203/rs.3.rs-40009/v1

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mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. mTORC1/2 components that stimulate mTOR kinase activity strongly affect neurodevelopment, but mTOR-inhibitory mTORC1/2 components do not, questioning the role of balanced mTOR regulation in neurodevelopment. We found a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 directly interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, known to inhibit mTORC1/2 but minimally affect neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Patient-derived Tanc2 mutations disable Tanc2 function, and human Tanc2 inhibits mTORC1/2. Therefore, Tanc2 represents a novel mTORC1/2 inhibitor with strong neurodevelopmental impacts, implicating mTOR inhibition in treating TANC2-related brain disorders and Tanc2 modulation in treating mTOR-related disorders.

Cellular & Molecular Neuroscience

Developmental Neuroscience

Brain development

signaling

mTOR

mTORC1

mTORC2

Tanc1

Tanc2

PSD-95

Deptor

human neurons

mTOR (mammalian target of rapamycin) signaling, a fundamental regulator of cellular growth and function ^1–4, controls the development and function of the nervous system ^5–12. mTOR signaling is also strongly associated with various brain disorders, including brain tumors, epilepsy, neurodegenerative disorders (e.g., Alzheimer’s and Parkinson’s diseases), neurocutaneous diseases (e.g., tuberous sclerosis complex and neurofibromatosis), intellectual disability, autism spectrum disorders (ASD), depression, and diseases of abuse (e.g., alcoholism) ^5–12.

mTOR nucleates the formation of mTOR complex-1 (mTORC1) and − 2 (mTORC2) by associating with both shared and distinct components. These include mLST8 and Deptor (for both mTORC1 and mTORC2), Raptor and PRAS40 (mTORC1 only), and Rictor, Protor, and Sin1 (mTORC2 only) ^1–4. These mTOR-interacting proteins coordinate the activity, subcellular localization, and substrate interactions of mTOR ^1–4. Loss of proteins that enable or stimulate mTORC1/2 function, namely mTOR, Raptor, Rictor and mLST, in mice leads to embryonic lethality ¹. However, loss of mTORC inhibitors (Deptor and PRAS40) has no significant impact on embryonic development or postnatal growth or survival ^13,14, leaving it unclear whether ‘balanced’ regulation of mTOR involving both mTOR activators and inhibitors is important for neural development.

Tanc2, a large (~ 200 kDa) multi-domain adaptor/scaffolding protein, is highly expressed in the brain ^15,16 and modestly expressed in other tissues (www.ebi.ac.uk/gxa/home) ¹⁷. Tanc2 is present at both synaptic and non-synaptic sites in neurons. Synaptic Tanc2 directly interacts with PSD-95 ^15,16, an abundant excitatory postsynaptic scaffolding protein ^18–20, and also promotes synaptic capture of motor protein-transported vesicles ²¹.

Functionally, the homozygous deletion of Tanc2 in mice leads to embryonic lethality ¹⁶. In humans, TANC2 mutations are extensively associated with various neuropsychiatric disorders, including intellectual disability, ASD, developmental delays, and schizophrenia ^17,22−30. Disruptive TANC2 mutations were recently identified in 20 different patients with neurodevelopmental symptoms associated with psychiatric disorders ¹⁷. These results suggest that Tanc2 is a critical regulator of brain development and function, but the underlying mechanisms remain unclear.

Abnormal behaviors and synaptic plasticity in Tanc2-mutant mice

To explore in vivo functions of Tanc2, we first characterized mice carrying a heterozygous deletion of the Tanc2 gene (Tanc2^+/–), encoding the Tanc2 protein (Fig. 1a). Tanc2^+/– mice, unlike homozygous Tanc2-mutant (Tanc2^–/–) mice¹⁶, do not exhibit embryonic lethality. However,Tanc2^+/– mice showed modestly decreased survival (~70% survival at postnatal day 7 [P7]), indicative of a dose-dependent impact of Tanc2 deletion on mouse development and survival.

In behavioral tests, adult male Tanc2^+/– mice (2–5 months; male) showed impaired spatial learning and memory in the Morris water maze, but normal novel-object recognition (Fig. 1b; Supplementary Fig. 1a). These mice also displayed hyperactivity and anxiolytic-like behavior, but largely normal social and depression-like behavior, and as neonates, showed suppressed ultrasonic vocalizations upon mother separation (Supplementary Fig. 1b–e and 2). Female adult Tanc2^+/– mice showed behavioral abnormalities similar to those of males (Supplementary Fig. 3). These results indicate that Tanc2^+/– mice are more relevant to human disease conditions.

To better understand the impaired spatial learning and memory in Tanc2^+/– mice, we examined synaptic plasticity in the hippocampus. Long-term potentiation (LTP) induced by high-frequency stimulation (HFS) was suppressed at Schaffer collateral-CA1 pyramidal cell (SC-CA1) synapses of Tanc2^+/– mice (7–8 weeks) (Fig. 1c). In contrast, LTP at a younger age (4–5 weeks) was normal (Supplementary Fig. 4a), suggestive of age-dependent LTP impairment. Basal excitatory synaptic transmission and presynaptic release were unaltered at SC-CA1 synapses of Tanc2^+/– mice (3–4 weeks) (Supplementary Fig. 4b,c). Long-term depression (LTD) induced by low-frequency stimulation (LFS) was also suppressed at SC-CA1 synapses of Tanc2^+/– mice (3–4 weeks), whereas mGluR-dependent LTD was normal (Fig. 1d; Supplementary Fig. 4d).

The abovementioned decrease in LTD at 3–4 weeks, which contrasts with the normal LTP at a similar age (4–5 weeks), cannot be explained by the decrease in currents of NMDA receptors (NMDARs), which are known to regulate both LTP and LTD ^31,32. We thus tested whether synaptic signaling downstream of NMDAR activation, also known to control LTP/LTD ^31,32, is altered by immunoblot analysis of neuronal signaling proteins.

mTOR hyperactivity in Tanc2-mutant mice

Intriguingly, mTOR activity, measured by mTOR phosphorylation (S2448) in immunoblot analyses, was markedly (~5-fold) increased in the whole brain of Tanc2^+/– pups (P14) without a change in total mTOR levels (Fig. 1e). This change was accompanied by hyper-phosphorylation of 4E-BP (T37/46), a downstream target of mTOR ^1-4, but not S6 (S235/236), another mTOR target^1-4, likely owing to compensatory changes occurring in heterozygous mice (see the stronger changes induced by homozygous Tanc2 deletion, below). In contrast, activities of PI3K (phosphoinositide 3-kinase), PTEN (phosphatase and tensin homolog) and TSC1/2 (tuberous sclerosis 1/2)—signaling proteins upstream of mTOR—were normal (Supplementary Fig. 5a), suggesting that they do not contribute to the mTOR hyperactivity.

Phosphorylation of Akt (S473), reflecting mTORC2 activity^1-4, was also strongly increased (Fig. 1f), suggesting that both mTORC1 and mTORC2 are hyperactive in the Tanc2^+/– brain (P14). Moreover, Ser-9 phosphorylation of GSK3b (glycogen synthase kinase 3b), a downstream target of Akt ³³ that promotes LTD ³², was increased (indicating reduced activity), in line with the suppressed LTD at Tanc2^+/– hippocampal synapses.

Interestingly, tests of Tanc2^+/– juveniles (P28) showed no significant changes in mTORC1 or mTORC2 activity, as indicated by immunoblot analyses of mTOR (S2448), S6 (S235/236), 4E-BP (T37/46), Akt (S473), and GSK3b (S9) (Supplementary Fig. 5b). This contrasts with results from Tanc2^+/– pups (P14) and suggests that the function of Tanc2 is age-dependent, consistent with the strong decrease in Tanc2 protein levels in the wild-type (WT) mouse brain after P14 ¹⁶.

Because the mTOR hyperactivity observed in Tanc2^+/– pups (P14) might represent indirect changes attributable to long-term deletion of Tanc2, we generated another Tanc2-mutant mouse line that carries a floxed Tanc2 allele (Tanc2^fl/fl) for use in creating a conditional gene knockout (cKO) (Supplementary Fig. 6). Injection of AAV1-hSyn-Cre-EGFP into the hippocampus of Tanc2^fl/fl pups (P5–14) to produce local homozygous knockout of Tanc2 induced hyper-phosphorylation of S6 (S235/236), 4E-BP (T37/46), Akt (S473), GSK3b (S9) and mTOR (S2248) (Fig. 1f), indicative of mTORC1 and mTORC2 hyperactivity. These results collectively suggest that Tanc2 deletion leads to mTORC1/2 hyperactivity at the pup (P7–14), but not juvenile (P21–28), stage.

Early rapamycin treatment normalizes LTP and behaviors in adult Tanc2^+/– mice

To gain mechanistic insight into how Tanc2 deletion induces mTOR hyperactivity, we first tested whether Tanc2 directly interacts with mTOR using protein-protein binding assays. Purified Tanc2 protein directly interacted with purified mTOR protein (Fig. 3a). Tanc2 also formed a complex with mTOR in the mouse brain (Fig. 3b,c). This interaction was mediated by multiple regions of Tanc2 protein and the C-terminal region of mTOR containing FRB and kinase domains (Fig. 3d–f). Here, mTOR was found to additionally interact with Tanc1, a relative of Tanc2 that is strongly expressed in late stages of rat brain development (>P14) and regulates synapse development, but is not critical for mouse development ^15,16.

The results described thus far suggest that Tanc2 directly interacts with mTOR, but do not speak to whether Tanc2 inhibits the kinase activity of mTOR. We tested this possibility by overexpressing Tanc2 in HEK293T cells, and found that this was sufficient to inhibit endogenous mTOR activity (Supplementary Fig. 7). Consistent with this, in vitro assays using purified proteins showed that Tanc2 directly inhibits mTOR kinase activity, as evidenced by decreased phosphorylation of the mTORC1 (mTOR + Raptor) target S6K in the presence of Tanc2 (Fig. 3g).

Serum and ketamine regulate the Tanc2–mTOR interaction

We next investigated whether Tanc2–mTOR interactions are regulated by extracellular influences, first testing serum, which is known to activate mTOR². Serum starvation promoted the colocalization and biochemical association of Tanc2 with mTOR in HEK293T cells within ~4 hours. This effect was reversed by serum replenishment for ~24 hours (Fig. 4a,b), suggesting that mTOR dissociates from Tanc2 upon serum stimulation. Moreover, the Tanc2–mTOR interaction induced by serum starvation was inhibited by rapamycin (Fig. 4c,d), suggesting that Tanc2 and rapamycin compete for binding to the mTOR FRB domain. Tanc1, which also associates with mTOR in the brain, interacted with mTOR in a serum- and rapamycin-dependent manner (Supplementary Fig. 8).

We next tested whether the Tanc1/2–mTOR interaction could be regulated in the brain of mice (P14) by ketamine-induced mTOR activation. Treatment with ketamine (10 mg/kg; i.p.), a fast-acting antidepressant known to stimulate mTOR signaling ³⁴, rapidly (~30–60 minutes) increased mTOR activity and promoted synaptic localization of mTOR-associated proteins as well as PSD-95 (Supplementary Fig. 9), as previously reported ³⁴. Importantly, ketamine treatment suppressed the Tanc1/2–mTOR interaction without affecting the Tanc1/2–PSD-95 interaction (Fig. 4e) ^15,16, suggesting that Tanc1/2 bridges mTOR to PSD-95 at the synapse in a regulated manner.

Tanc2, Deptor, and Tanc1 distinctly inhibit mTORC1/2 in early- and late-stage neurons

Because Deptor, similar to Tanc2, also binds and inhibits mTORC1/2 ³⁵, we tested whether Tanc2 and Deptor show overlapping or distinct spatiotemporal expression patterns. Immunoblot analyses using cultured neurons and mouse brain extracts showed that Tanc2 protein was more strongly expressed in early stages (embryonic and early postnatal) and was less enriched at synapses (Supplementary Fig. 10). In contrast, Deptor and Tanc1 showed progressive increases in expression across postnatal stages and stronger synaptic enrichment in both cultured neurons and mouse brains, a pattern similar to that reported for rat Tanc1 and Tanc2 ^15,16.

These results suggest that Tanc2 and Deptor/Tanc1 may distinctly inhibit mTOR activity at different developmental stages. We thus sought to acutely knockdown Tanc2 and Deptor/Tanc1 in cultured mouse hippocampal neurons during early (days in vitro [DIV] 7–14) and late (DIV21–28) stages. Early-stage Tanc2 knockdown induced hyper-phosphorylation of S6 (S235/236), 4E-BP (T37/46), Akt (S473), and GSK3b (S9) (Fig. 5a–c), suggestive of mTORC1 and mTORC2 hyperactivity. Akt (T308) phosphorylation was unaltered, in line with the normal activities of mTOR-upstream proteins in Tanc2^+/– mice (Supplementary Fig. 5). In contrast, late-stage Tanc2 knockdown had no effect on these phosphorylation events (Fig. 5d–f).

Late-stage, but not early-stage, knockdown of Deptor induced hyper-phosphorylation of S6 (S235/236), 4E-BP (T37/46), Akt (S473) and GSK3b (S9) (Fig. 5a–f), suggestive of mTORC1 and mTORC2 hyperactivity. In addition, late-stage, but not early-stage, knockdown of Tanc1 induced similar hyper-phosphorylation of S6 (S235/236), 4E-BP (T37/46), Akt (S473), and GSK3b (S9) (Fig. 5d–f). Tanc2 and Deptor double-knockdown did not produce additive effects at early or late stages, except with respect to early-stage (P7–14) mTOR phosphorylation (Fig. 5a–f). These results suggest that Tanc2 and Deptor/Tanc1 distinctly inhibit mTORC1/2 signaling at early and late stages of mouse brain development, respectively, in line with the embryonic lethality of Tanc2, but not Deptor or Tanc1, KO mice ^14,16.

To determine whether neurons or glial cells are more important for Tanc2-dependent mTOR inhibition, we selectively knocked down Tanc2 in neuron- or glia-enriched early-stage cultured hippocampal neurons (DIV7–14). Neuronal, but not glial, Tanc2 knockdown induced mTOR hyperactivity, and, in line with this, Tanc2 expression was much weaker in glial cells (Supplementary Fig. 11), suggesting that Tanc2 is more important for mTOR inhibition in neurons than in glial cells at early stages.

Patient-derivedTanc2 mutations suppress Tanc2-dependent mTOR inhibition

To determine whether there is a relationship between Tanc2-dependent mTOR inhibition and human brain disorders, we first tested whether specific Tanc2 mutations associated with intellectual disability, schizophrenia, and ASD identified in humans (R760C, A794V, and H1689R) ^22,23,26 affected interactions with mTOR or inhibition of mTOR activity (Fig. 6a). Coimmunoprecipitation experiments showed that, of these mutants, only Tanc2-H1689R failed to biochemically associate with mTOR in HEK293T cells (Fig. 6b,c); however, all three Tanc2 mutants failed to inhibit mTOR activity (Fig. 6d–f). Therefore, patient-derived Tanc2 mutations disrupt the mTOR-binding and/or mTOR-inhibitory activity of Tanc2.

TANC2 in human neurons inhibits mTORC1 and mTORC2

Finally, we tested whether Tanc2 inhibits mTOR activity in human neurons. To this end, we knocked down TANC2 in human neural progenitor cells (NPCs) developing into mature neurons for 2 weeks using two independent TANC2 knockdown constructs. Both TANC2 knockdown constructs similarly increased phosphorylation of S6 (S235/236), 4E-BP (T37/46), and GSK3b (S9), although they exerted mixed effects on Akt (S473) phosphorylation (Fig. 6g–i). mTOR phosphorylation was unaltered, similar to the results from mouse neurons (Fig. 5). These results collectively suggest that Tanc2 inhibits mTORC1/2 in both human and mouse neurons.

The present study suggests that Tanc2 is a novel and regulated mTOR inhibitor that has strong neurodevelopmental impacts and therapeutic potential. The first important conclusion from our results is that Tanc2 binds to mTOR. In support of this, Tanc2 forms a complex with mTOR in heterologous cells and in the mouse brain. More directly, purified Tanc2 proteins form a complex with purified mTOR proteins. Tanc2 uses its multiple domains to associate with mTOR, whereas mTOR binds to Tanc2 through its C-terminal region, containing the FRB, kinase, and FATC domains. The latter is further supported by that rapamycin, known to bind to the FRB domain of mTOR, blocks the colocalization and biochemical association between Tanc2 and mTOR. This result suggests the possibility that rapamycin could be used to block the Tanc2–mTOR interaction and to promote mTOR activity in various contexts such as decreased mTOR activity in human disorders.

Tanc2 binds to mTOR in a regulated manner. The presence of serum, well known to activate mTOR, weakens the colocalization and biochemical association between Tanc2 and mTOR. In addition, ketamine, a fast-acting antidepressant known to promote excitatory synapse functions and mTOR activity ³⁴, inhibits the Tanc2–mTOR interaction in the mouse brain. These results suggest that Tanc2 inhibits mTOR in a regulated manner to coordinate mTOR activity under various nutritional states and during brain development and neuronal or synaptic activities. Specific mechanisms that underlie the regulated Tanc2-mTOR interactions remain to be determined although they could be posttranslational modifications of mTOR or Tanc2 at binding interfaces or regulatory domains.

Perhaps the most important conclusion of the present study is that Tanc2 inhibits mTOR. This is supported by multiple lines of in vitro and vivo evidence. Most directly, purified Tanc2 inhibits the kinase activity of mTOR, as shown by the suppression of mTOR-dependent phosphorylation of an mTOR substrate (S6K). In addition, Tanc2 overexpressed in HEK293T cells inhibits mTOR, while mutant Tanc2 proteins carrying human mutations fail to bind and inhibit mTOR. Moreover, acute knockdown of Tanc2 increases mTOR activity in cultured mouse neurons at around developmental stages of strong Tanc2 expression. Tanc2^+/− mice show increased mTOR activity in both mTORC1 and mTORC2 complexes. In addition, cre-dependent acute knockout of Tanc2 in an independent Tanc2-mutant mouse line increases mTOR activity in mTORC1/2. In human neurons, Tanc2 knockdown increases mTOR activity in mTORC1/2 in neural progenitor cells developing into neurons. These results strongly suggest that Tanc2 binds to and inhibits mTOR in mouse and human neurons at early stages.

In addition to Tanc2, Tanc1 interacts with and inhibits mTOR in a rapamycin-dependent manner. Tanc1 expression sharply increases during postnatal stages of mouse brain development, whereas Tanc2 expression is relatively stronger at earlier stages. Deptor, a known mTOR inhibitor, also shows strong late-stage expression, similar to Tanc1. It is therefore possible that Tanc2, Tanc1, and Deptor distinctly inhibit mTOR across different developmental stages. Indeed, our results indicate that Tanc2 and Tanc1/Deptor inhibit mTOR more strongly at around postnatal weeks 2 and 4, respectively. These results are in line with the differential impacts of homozygous Tanc2 and Tanc1/Deptor deletions in mice, where the deletion of Tanc2, but not Tanc1 or Deptor, leads to embryonic lethality ^14,16.

Tanc2 and Tanc1 interact with the PSD-95 family of scaffolding proteins, known to mediate the molecular organization of multi-protein complexes at cell-to-cell junctions such as neuronal synapses in order to couple receptor activations with signaling pathways ^18,19. Therefore, Tanc2 and Tanc1 may recruit mTORC1/2 complexes to PSD-95-based multiple protein complexes at excitatory postsynaptic sites. In line with this idea, Tanc2 has been suggested to recruit cargo dense core vesicles driven by the KIF1A motor protein to excitatory synapses ²¹. Synaptically localized mTORC1/2 may be inhibited by local Tanc2 until mTOR activity is increased by the activation of synaptic receptors such as TrkB and mGluRs ³⁶. The four known members of the PSD-95 family (PSD-95, PSD-93, SAP102, and SAP97) display differential spatiotemporal expression patterns; i.e. PSD-95 and PSD-93 are more abundant at later developmental stages whereas SAP102 expression is stronger at earlier stages. It is therefore possible that Tanc2 and Tanc1 may coordinate mTORC1/2 signaling at both synaptic and non-synpatic sites of PSD-95-enriched multi-protein complexes in developing neural and non-neural tissues.

The synaptic and behavioral phenotypes of Tanc2^+/− mice implicate Tanc2 in the regulation of synaptic plasticity and behaviors, including LTP, learning and memory, hyperactivity, and anxiety-like behavior, all of which are reversed by rapamycin-dependent mTOR inhibition. In humans, Tanc2 mutations have been extensively associated with various neurodevelopmental and neuropsychiatric disorders, including intellectual disability, schizophrenia, and ASD ^17,22−30. These results, together with the embryonic lethality in Tanc2^−/− mice and strongly increased mTOR activity in Tanc2^+/− mice, suggest that Tanc2 regulates normal bran development and function by coordinating mTOR inhibition, and that rapamycin-dependent mTOR inhibition could be used to treat human patients with Tanc2 mutations and resulting mTOR hyperactivity. In addition, modulation of Tanc2 activity, i.e. anti-sense Tanc2 knockdown or virus-mediated Tanc2 overexpression, could be used to treat various mTOR-related brain disorders ^{5–7,37−39}. These therapeutic potentials extend to non-neural tissues and non-brain mTOR-related disorders such as metabolic diseases ^1,2 because Tanc2 and Tanc1 are expressed in various non-neural tissues in mice and humans (www.ebi.ac.uk/gxa/home) ^16,17.

In conclusion, our study reports that Tanc2 is a novel and regulated mTOR inhibitor with strong neurodevelopmental impacts, supporting the general notion that balanced mTOR regulation involving both mTOR activators and inhibitors is important for normal brain development and function. In addition, our results suggest that mTOR inhibition could be an effective strategy for treating human individuals with TANC2 mutations suffering from neuropsychiatric disorders, including intellectual disability, ASD, developmental delays, and schizophrenia. In addition, Tanc2 modulations promoting or suppressing mTOR signaling could have therapeutic potential for the treatment of various mTOR-related peripheral and brain disorders.

Acknowledgments

We would like to Dr. Kwang-Wook Choi in the Department of Biological Sciences at KAIST for thoughtful comments on the manuscript. This work was supported by the the Ministry of Health & Welfare (HI18C1077 to J.H.), Institute for Basic Science (IBS-R002-A1 to J.H.), NRF Grant 2013M3C7A1056732 (to H.K.), the Future Systems Healthcare Project of KAIST (to S.P.), and the Institute for Basic Science (IBS-R002-D1 to E.K.).

Author contributions

S.K. and S.L. designed experiments and analyzed data; Y.L., H.K., and S.K. generated mice; S.K., Y.K., J.P., and H.J. conducted mouse behavioral experiments and analysis; S.K. and J.P. performed biochemical experiments and analysis; S.K., Y.K., W.S., J.D.R., K.K., and S.M.U. conducted slice electrophysiology experiments and analysis; S.L. performed cultured neuron experiments, protein-protein interaction experiments, and in vitro kinase assays; S.L. and K.K. performed virus injection experiments; D.W., S.L., C.Y. and M.L. performed imaging experiments and analysis; D.K. and S.L. performed human neuron experiments; S.K., J.H., W.D.H., and E.K. wrote the manuscript.

Declaration of interests

The authors declare that they have no competing financial interests.

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