mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex

Abstract

Outer radial glial (oRG) cells are a population of neural stem cells prevalent in the developing human cortex that contribute to its cellular diversity and evolutionary expansion. The mammalian Target of Rapamycin (mTOR) signaling pathway is active in human oRG cells. Mutations in mTOR pathway genes are linked to a variety of neurodevelopmental disorders and malformations of cortical development. We find that dysregulation of mTOR signaling specifically affects oRG cells, but not other progenitor types, by changing the actin cytoskeleton through the activity of the Rho-GTPase, CDC42. These effects change oRG cellular morphology, migration, and mitotic behavior, but do not affect proliferation or cell fate. Thus, mTOR signaling can regulate the architecture of the developing human cortex by maintaining the cytoskeletal organization of oRG cells and the radial glia scaffold. Our study provides insight into how mTOR dysregulation may contribute to neurodevelopmental disease.

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

“…Newer rodent models using IUE to focally express or suppress mTORC1 pathway regulating genes in the cortex (discussed more below), as well as Tsc2 and Depdc5 zebrafish models (Kim S. H. et al, 2011;de Calbiac et al, 2018;Swaminathan et al, 2018), also recapitulate many of the mTORopathy phenotypes. Recent models also include patient-derived induced pluripotent stem cells (IPSCs) and cortical organoids, which provide the advantage of studying mTOR function in human cell populations (Blair et al, 2018;Andrews et al, 2020;Dang et al, 2020;Eichmüller et al, 2020). Both transgenic and IUE-based animal models as well as in vitro models have been vital for mechanistic and preclinical drug studies.…”

BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models

“…In particular, β-actin mRNA is locally translated near focal adhesions 83 and interestingly, it is the newly synthesized β-actin that is preferentially used in focal adhesion maturation 56 . While global β-actin is less sensitive to cap-dependent translation perturbation [84][85][86][87][88] , this has recently been demonstrated to be cell type and stress dependent [89][90][91] . Indeed, during axon guidance, localized β-actin translation is associated with localized 4E-BP1 hyperphosphorylation 92 .…”

Morphological and Calcium Signaling Alterations of Neuroglial Cells in Cerebellar Cortical Dysplasia Induced by Carmustine

“…A previous study reported that the absence of the ataxia telangiectasia mutated (ATM) protein in cerebellar astrocytes in culture reshapes their morphology, producing a reduction in the length and number of processes, which in turn negatively regulates the mammalian target of rapamycin (mTOR) pathway [ 33 ]. In addition, it has also been reported that manipulation of mTOR signaling disrupts the glial scaffold in primary cortical and organoid cultures [ 56 ]. These structural changes are associated with abnormal developmental maturation [ 33 , 35 , 36 ] which also alters calcium signaling and affects the cerebellar networks.…”