MTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization.

Qian Shi,Anna Marie Taylor,Julia Saifetiarova,Manzoor A Bhat

doi:10.3389/fncel.2018.00201

Qian Shi, Anna Marie Taylor + Show 2 more

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https://doi.org/10.3389/fncel.2018.00201

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Abstract

Mutations in human tuberous sclerosis complex (TSC) genes TSC1 and TSC2 are the leading causes of developmental brain abnormalities and large tumors in other tissues. Murine Tsc1/2 have been shown to negatively regulate the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in most tissues, and this pathway has been shown to be essential for proper oligodendrocytes/Schwann cell differentiation and myelination. Here, we report that ablation of Tsc1 gene specifically in oligodendrocytes/Schwann cells activates mTORC1 signaling resulting in severe motor disabilities, weight loss, and early postnatal death. The mutant mice of either sex showed reduced myelination, disrupted paranodal domains in myelinated axons, and disorganized unmyelinated Remak bundles. mRNA and protein expression analyses revealed strong reduction in the RNA–binding protein Quaking (Qk) and the 155 kDa glial Neurofascin (NfascNF155). Re-introduction of exogenous Qk gene in Tsc1 mutant oligodendrocytes restored NfascNF155 protein levels indicating that Qk is required for the stabilization of NfascNF155 mRNA. Interestingly, injection of Rapamycin, a pharmacological mTORC1 inhibitor, to pregnant mothers increased the lifespan of the mutant offspring, restored myelination as well as the levels of Qk and NfascNF155, and consequently the organization of the paranodal domains. Together our studies show a critical role of mTORC1 signaling in the differentiation of myelinating glial cells and proper organization of axonal domains and provide insights into TSC-associated myelinated axon abnormalities.

Highlights

The mammalian target of Rapamycin is a central player in mTOR signaling pathway, governing the cellular growth and metabolic homeostasis in response to many growth factors, cellular energy status and amino-acid levels (Saxton and Sabatini, 2017a). mammalian target of rapamycin complex 1 (mTORC1) is activated by Rheb, which is inhibited by a GTPase-activating heterodimeric mTORC1 Signaling Regulates Paranodal Organization protein complex, formed by tuberous sclerosis complex (TSC) proteins, Hamartin (TSC1) and Tuberin (TSC2)
Given the role of mTORC1 signaling in regulating protein translation, it is surprising to find that activation of mTORC1 by Tsc1 or Tsc2 deletion in oligodendrocyte progenitor cells (OPCs) leads to hypomyelination, which has been recently reported (LebrunJulien et al, 2014; Carson et al, 2015; Jiang et al, 2016)
To better understand the role of mTORC1 signaling in myelinating glia during development, we generated Tsc1 conditional knockout mice by breeding Tsc1Flox/Flox(designated Tsc1Flox) mice with the 2’,3’-cyclic nucleotide 3’-phosphodiesterase (Cnp)-Cre mice, which cause the deletion of exon 17 and 18 in theTsc1 locus in OLs and spinal cord (SC) (Figure 1A)

Summary

Introduction

The mammalian target of Rapamycin (mTOR) is a central player in mTOR signaling pathway, governing the cellular growth and metabolic homeostasis in response to many growth factors, cellular energy status and amino-acid levels (Saxton and Sabatini, 2017a). mTORC1 is activated by Rheb, which is inhibited by a GTPase-activating heterodimeric mTORC1 Signaling Regulates Paranodal Organization protein complex, formed by tuberous sclerosis complex (TSC) proteins, Hamartin (TSC1) and Tuberin (TSC2). Given the role of mTORC1 signaling in regulating protein translation, it is surprising to find that activation of mTORC1 by Tsc or Tsc deletion in oligodendrocyte progenitor cells (OPCs) leads to hypomyelination, which has been recently reported (LebrunJulien et al, 2014; Carson et al, 2015; Jiang et al, 2016). It appears that a delicate balance of mTOR signaling is required for the differentiation of oligodendrocytes, as either hyper-activation or inactivation of mTORC1 signaling leads to hypomyelination and disruption of OPC differentiation. A recent study showed that Tsc depletion from OL progenitor cells accelerated remyelination; Tsc deletion from differentiated OLs slowed remyelination, again suggesting a rather complex role of mTOR signaling in determining OL differentiation and myelination (McLane et al, 2017)

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