Neocortical Expansion Due to Increased Proliferation of Basal Progenitors Is Linked to Changes in Their Morphology

Kalebic, Nereo; Gilardi, Carlotta; Stepien, Barbara K.; Wilsch‐Bräuninger, Michaela; Long, Katherine R.; Namba, Tsuneo; Florio, Marta; Langen, Barbara; Lombardot, Benoît; Shevchenko, Anna; Kilimann, Manfred W.; Kawasaki, Hiroshi; Wimberger, Pauline; Huttner, Wieland B.

doi:10.1016/j.stem.2019.02.017

Cited by 129 publications

(204 citation statements)

References 54 publications

(126 reference statements)

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“…Further, we identified a unique role for the mTOR signaling pathway in regulating oRG morphology and migration. The polar morphology of oRG cells, with an elongated basal process, not only provides a mechanism for the dynamic division and migratory behavior that promotes progenitor expansion (Betizeau et al, 2013;Gertz & Kriegstein, 2015;Kalebic et al, 2019;LaMonica et al, 2013), but also creates a scaffold for the migration of cortical neurons. Our results show that mTOR signaling in oRG cells is tightly regulated to maintain cell morphology.…”

Section: Discussionmentioning

confidence: 99%

“…oRG cells undergo mitotic somal translocation (MST), where the nucleus moves rapidly along the basal process towards the pial surface prior to mitosis (Hansen et al, 2010). The migration and MST behaviors of oRG cells depend greatly on the integrity of the basal process (Betizeau et al, 2013;Kalebic et al, 2019;Ostrem et al, 2014a). oRG basal processes also function as a glial scaffold to support neuronal migration (Gertz & Kriegstein, 2015;Nowakowski et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

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

Andrews

Subramanian

Kriegstein

2020

Preprint

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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 GTPase, CDC42. These effects change oRG cellular morphology, migration, and mitotic behavior. 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Andrews

Subramanian

Kriegstein

2020

Preprint

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“…A few genes have been found to be associated with the expansion of cerebral cortex in human evolution (Florio et al, 2015;Hansen et al, 2010;Kalebic et al, 2019;Long et al, 2018;Mekel-Bobrov et al, 2005;Wang et al, 2011), one of which encodes a protein targeted to mitochondria, implicating metabolic changes in human brain evolution (Namba et al, 2020). It is unclear whether the species differences in metabolism we found are specific to astrocytes.…”

Section: Species Differences In Energy Metabolism In Astrocytes and Omentioning

confidence: 99%

Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Pan

Godoy

et al. 2020

Preprint

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Human-mouse differences are a major barrier in translational research.Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. However, the similarities and differences between human and mouse astrocytes are largely unknown. Combining analyses of acutely purified astrocytes, experiments using serum-free cultures of primary astrocytes, and xenografted chimeric mice, we found extensive conservation in astrocytic gene expression between human and mouse. However, genes involved in defense response and metabolism showed species differences. Human astrocytes exhibited greater susceptibility to oxidative stress than mouse astrocytes, due to differences in mitochondria physiology and detoxification pathways. Mouse astrocytes, but not human astrocytes, activate a molecular program for neural repair under hypoxia. Human astrocytes, but not mouse astrocytes, activate the antigen presentation pathway under inflammatory conditions. These species-dependent properties of astrocytes may contribute to differences between mouse models and human neurological and psychiatric disorders.

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“…Importantly, the subventricular zone is vastly expanded in humans as compared to rodents, partly due to the enhanced proliferative capacity and morphological differences of human INPs. 148,149 The INPs located in the outer subventricular zone contribute to the majority of cortical neurons in the human brain. There are many factors, both intrinsic and extrinsic, that regulate proliferation and neurogenesis in the mammalian and human brain.…”

Section: Proliferation and Neurogenesismentioning

confidence: 99%

Probing disrupted neurodevelopment in autism using human stem cell‐derived neurons and organoids: An outlook into future diagnostics and drug development

Yang

Shcheglovitov

2019

Developmental Dynamics

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Autism spectrum disorders (ASDs) represent a spectrum of neurodevelopmental disorders characterized by impaired social interaction, repetitive or restrictive behaviors, and problems with speech. According to a recent report by the Centers for Disease Control and Prevention, one in 68 children in the US is diagnosed with ASDs. Although ASD-related diagnostics and the knowledge of ASD-associated genetic abnormalities have improved in recent years, our understanding of the cellular and molecular pathways disrupted in ASD remains very limited. As a result, no specific therapies or medications are available for individuals with ASDs. In this review, we describe the neurodevelopmental processes that are likely affected in the brains of individuals with ASDs and discuss how patient-specific stem cellderived neurons and organoids can be used for investigating these processes at the cellular and molecular levels. Finally, we propose a discovery pipeline to be used in the future for identifying the cellular and molecular deficits and developing novel personalized therapies for individuals with idiopathic ASDs.

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Neocortical Expansion Due to Increased Proliferation of Basal Progenitors Is Linked to Changes in Their Morphology

Cited by 129 publications

References 54 publications

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

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

Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Probing disrupted neurodevelopment in autism using human stem cell‐derived neurons and organoids: An outlook into future diagnostics and drug development

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