Faculty Opinions recommendation of Molecular identity of human outer radial glia during cortical development.

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

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

10.7554/elife.58737.sa1 ◽

2020 ◽

Author(s):

Anita Bhattacharyya

Keyword(s):

Radial Glia ◽

Mtor Signaling ◽

Human Cortex ◽

Outer Radial Glia ◽

And Migration

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Neddylation is critical to cortical development by regulating Wnt/β-catenin signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005395117 ◽

2020 ◽

Vol 117 (42) ◽

pp. 26448-26459 ◽

Cited By ~ 1

Author(s):

Lei Zhang ◽

Hongyang Jing ◽

Haiwen Li ◽

Wenbing Chen ◽

Bin Luo ◽

...

Keyword(s):

Wnt Signaling ◽

Protein Modification ◽

Radial Glia ◽

Critical Role ◽

Cortical Development ◽

Nuclear Accumulation ◽

Progressive Reduction ◽

Intermediate Progenitors

Wnt signaling plays a critical role in production and differentiation of neurons and undergoes a progressive reduction during cortical development. However, how Wnt signaling is regulated is not well understood. Here we provide evidence for an indispensable role of neddylation, a ubiquitylation-like protein modification, in inhibiting Wnt/β-catenin signaling. We show that β-catenin is neddylated; and inhibiting β-catenin neddylation increases its nuclear accumulation and Wnt/β-catenin signaling. To test this hypothesis in vivo, we mutated Nae1, an obligative subunit of the E1 for neddylation in cortical progenitors. The mutation leads to eventual reduction in radial glia progenitors (RGPs). Consequently, the production of intermediate progenitors (IPs) and neurons is reduced, and neuron migration is impaired, resulting in disorganization of the cerebral cortex. These phenotypes are similar to those of β-catenin gain-of-function mice. Finally, suppressing β-catenin expression is able to rescue deficits of Nae1 mutant mice. Together, these observations identified a mechanism to regulate Wnt/β-catenin signaling in cortical development.

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Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1605740113 ◽

2016 ◽

Vol 113 (40) ◽

pp. 11330-11335 ◽

Cited By ~ 21

Author(s):

Tiffany V. Lin ◽

Lawrence Hsieh ◽

Tomoki Kimura ◽

Taylor J. Malone ◽

Angélique Bordey

Keyword(s):

Neurodevelopmental Disorders ◽

Cortical Neurons ◽

Radial Glia ◽

Mammalian Target Of Rapamycin ◽

Initiation Factor ◽

Translational Repressor ◽

Molecular Identity ◽

Eukaryotic Initiation Factor 4E ◽

Intracellular Process ◽

Abnormal Brain

Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is a shared molecular hallmark in several neurodevelopmental disorders characterized by abnormal brain cytoarchitecture. The mechanisms downstream of mTORC1 that are responsible for these defects remain unclear. We show that focally increasing mTORC1 activity during late corticogenesis leads to ectopic placement of upper-layer cortical neurons that does not require altered signaling in radial glia and is accompanied by changes in layer-specific molecular identity. Importantly, we found that decreasing cap-dependent translation by expressing a constitutively active mutant of the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) prevents neuronal misplacement and soma enlargement, while partially rescuing dendritic hypertrophy induced by hyperactive mTORC1. Furthermore, overactivation of translation alone through knockdown of 4E-BP2 was sufficient to induce neuronal misplacement. These data show that many aspects of abnormal brain cytoarchitecture can be prevented by manipulating a single intracellular process downstream of mTORC1, cap-dependent translation.

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

10.1101/2020.05.14.095117 ◽

2020 ◽

Author(s):

Madeline G. Andrews ◽

Lakshmi Subramanian ◽

Arnold R. Kriegstein

Keyword(s):

Radial Glia ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Human Cortex ◽

Neurodevelopmental Disease ◽

Outer Radial Glia ◽

Radial Glial ◽

And Migration ◽

Insight Into ◽

Mitotic Behavior

AbstractOuter 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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Neuronal Delamination and Outer Radial Glia Generation in Neocortical Development

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.623573 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ayano Kawaguchi

Keyword(s):

Progenitor Cells ◽

Neural Progenitor Cells ◽

Radial Glia ◽

Adherens Junction ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Microtubule Assembly ◽

Apical Surface ◽

Neocortical Development ◽

Outer Radial Glia

During neocortical development, many neuronally differentiating cells (neurons and intermediate progenitor cells) are generated at the apical/ventricular surface by the division of neural progenitor cells (apical radial glial cells, aRGs). Neurogenic cell delamination, in which these neuronally differentiating cells retract their apical processes and depart from the apical surface, is the first step of their migration. Since the microenvironment established by the apical endfeet is crucial for maintaining neuroepithelial (NE)/aRGs, proper timing of the detachment of the apical endfeet is critical for the quantitative control of neurogenesis in cerebral development. During delamination, the microtubule–actin–AJ (adherens junction) configuration at the apical endfeet shows dynamic changes, concurrent with the constriction of the AJ ring at the apical endfeet and downregulation of cadherin expression. This process is mediated by transcriptional suppression of AJ-related molecules and multiple cascades to regulate cell adhesion and cytoskeletal architecture in a posttranscriptional manner. Recent advances have added molecules to the latter category: the interphase centrosome protein AKNA affects microtubule dynamics to destabilize the microtubule–actin–AJ complex, and the microtubule-associated protein Lzts1 inhibits microtubule assembly and activates actomyosin systems at the apical endfeet of differentiating cells. Moreover, Lzts1 induces the oblique division of aRGs, and loss of Lzts1 reduces the generation of outer radial glia (oRGs, also called basal radial glia, bRGs), another type of neural progenitor cell in the subventricular zone. These findings suggest that neurogenic cell delamination, and in some cases oRG generation, could be caused by a spectrum of interlinked mechanisms.

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Outer Radial Glia–Like Cells May Promote Glioblastoma Invasiveness

Cancer Discovery ◽

10.1158/2159-8290.cd-rw2020-006 ◽

2020 ◽

Vol 10 (2) ◽

pp. 173.1-173

Keyword(s):

Radial Glia ◽

Outer Radial Glia

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Biphasic roles of hedgehog signaling in the production and self-renewal of outer radial glia in the ferret cerebral cortex

10.1101/2021.04.12.439562 ◽

2021 ◽

Author(s):

Shirui Hou ◽

Wan-Ling Ho ◽

Lei Wang ◽

Bryan Kuo ◽

Jun Young Park ◽

...

Keyword(s):

Hedgehog Signaling ◽

Radial Glia ◽

Superficial Layer ◽

Cellular Mechanisms ◽

Self Renewal ◽

Layer Neuron ◽

Outer Radial Glia ◽

Hh Signaling ◽

Necessary And Sufficient

The neocortex, the center for higher brain function, emerged in mammals and expanded in the course of evolution. The expansion of outer radial glia (oRGs) and intermediate progenitor cells (IPCs) plays key roles in the expansion and consequential folding of the neocortex. Therefore, understanding the mechanisms of oRG and IPC expansion is important for understanding neocortical development and evolution. By using mice and human cerebral organoids, we previously revealed that hedgehog (HH) signaling expands oRGs and IPCs. Nevertheless, it remained to be determined whether HH signaling expanded oRGs and IPCs in vivo in gyrencephalic species, in which oRGs and IPCs are naturally expanded. Here, we show that HH signaling is necessary and sufficient to expand oRGs and IPCs in ferrets, a gyrencephalic species, through conserved cellular mechanisms. HH signaling increases oRG-producing division modes of ventricular radial glia (vRGs), oRG self-renewal, and IPC proliferation. Notably, HH signaling affects vRG division modes only in an early restricted phase before superficial-layer neuron production peaks. Beyond this restricted phase, HH signaling promotes oRG self-renewal. Thus, HH signaling expands oRGs and IPCs in two distinct but continuous phases during cortical development.

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

eLife ◽

10.7554/elife.58737 ◽

2020 ◽

Vol 9 ◽

Author(s):

Madeline G Andrews ◽

Lakshmi Subramanian ◽

Arnold R Kriegstein

Keyword(s):

Cell Fate ◽

Radial Glia ◽

Rho Gtpase ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Human Cortex ◽

Neurodevelopmental Disease ◽

Outer Radial Glia ◽

Radial Glial ◽

And Migration

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.

Download Full-text