Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini

Susana I. Ramos; Eugene V. Makeyev; Marcelo Salierno; Takashi Kodama; Yasuhiko Kawakami; Setsuko Sahara

doi:10.1016/j.devcel.2020.01.036

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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Upregulation of neurovascular communication through filamin abrogation promotes ectopic periventricular neurogenesis

eLife ◽

10.7554/elife.17823 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 3

Author(s):

Shauna L Houlihan ◽

Alison A Lanctot ◽

Yan Guo ◽

Yuanyi Feng

Keyword(s):

Neuronal Migration ◽

Cortical Neurons ◽

Neural Progenitor Cells ◽

Radial Glia ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Intermediate Progenitors ◽

Neuronal Fate ◽

Cerebral Cortical Neurons

Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs’ neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs. We show that by collaborating with β-arrestin, Flna maintains the homeostatic signaling between the vasculature and NPCs, and loss of this function results in escalated Vegfa and Igf2 signaling, which exacerbates both EMT and angiogenesis to further potentiate IPs’ neurogenesis. These results suggest that the neurogenic potential of IPs may be boosted in vivo by manipulating Flna-mediated neurovascular communication.

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Lis1 mutation prevents basal radial glia-like cell production in the mouse

10.1101/2020.10.10.334508 ◽

2020 ◽

Author(s):

Maxime Penisson ◽

Shinji Hirotsune ◽

Fiona Francis ◽

Richard Belvindrah

Keyword(s):

Mitotic Spindle ◽

Neuronal Migration ◽

Radial Glia ◽

Ventricular Zone ◽

Specific Gene ◽

Wild Type ◽

Intermediate Progenitors ◽

Gene Coding ◽

Outer Radial Glia

AbstractHuman cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. The LIS1 gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved by in utero electroporation of a hominoid-specific gene TBC1D3 (coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed that TBC1D3 expression in wild-type (WT) brain generates numerous Pax6+ bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygote Lis1 mutant brains. Our novel results show that Lis1 depletion in the forebrain from E9.5 prevented subsequent TBC1D3-induced bRG-like cell amplification. Indeed, we observe disruption of the ventricular zone (VZ) in the mutant. Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that perturbation of Lis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.

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Transcriptional priming as a conserved mechanism of lineage diversification in the developing mouse and human neocortex

Science Advances ◽

10.1126/sciadv.abd2068 ◽

2020 ◽

Vol 6 (45) ◽

pp. eabd2068

Author(s):

Zhen Li ◽

William A. Tyler ◽

Ella Zeldich ◽

Gabriel Santpere Baró ◽

Mayumi Okamoto ◽

...

Keyword(s):

Glial Cells ◽

Radial Glia ◽

Radial Glial Cells ◽

Human Neocortex ◽

Intermediate Progenitors ◽

Cell Diversity ◽

Radial Glial ◽

The Rich ◽

Lineage Diversification

How the rich variety of neurons in the nervous system arises from neural stem cells is not well understood. Using single-cell RNA-sequencing and in vivo confirmation, we uncover previously unrecognized neural stem and progenitor cell diversity within the fetal mouse and human neocortex, including multiple types of radial glia and intermediate progenitors. We also observed that transcriptional priming underlies the diversification of a subset of ventricular radial glial cells in both species; genetic fate mapping confirms that the primed radial glial cells generate specific types of basal progenitors and neurons. The different precursor lineages therefore diversify streams of cell production in the developing murine and human neocortex. These data show that transcriptional priming is likely a conserved mechanism of mammalian neural precursor lineage specialization.

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Extracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity

Nature Communications ◽

10.1038/s41467-021-26447-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Christina Kyrousi ◽

Adam C. O’Neill ◽

Agnieska Brazovskaja ◽

Zhisong He ◽

Pavel Kielkowski ◽

...

Keyword(s):

Radial Glia ◽

De Novo ◽

Temporal Expression ◽

Intermediate Progenitors ◽

And Migration ◽

Human Fetal Tissues ◽

And Function ◽

Gene Expression Alterations ◽

Differentiation Gene

AbstractBasal progenitors (BPs), including intermediate progenitors and basal radial glia, are generated from apical radial glia and are enriched in gyrencephalic species like humans, contributing to neuronal expansion. Shortly after generation, BPs delaminate towards the subventricular zone, where they further proliferate before differentiation. Gene expression alterations involved in BP delamination and function in humans are poorly understood. Here, we study the role of LGALS3BP, so far known as a cancer biomarker, which is a secreted protein enriched in human neural progenitors (NPCs). We show that individuals with LGALS3BP de novo variants exhibit altered local gyrification, sulcal depth, surface area and thickness in their cortex. Additionally, using cerebral organoids, human fetal tissues and mice, we show that LGALS3BP regulates the position of NPCs. Single-cell RNA-sequencing and proteomics reveal that LGALS3BP-mediated mechanisms involve the extracellular matrix in NPCs’ anchoring and migration within the human brain. We propose that its temporal expression influences NPCs’ delamination, corticogenesis and gyrification extrinsically.

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Multipotent radial glia progenitors and fate-restricted intermediate progenitors sequentially generate diverse cortical interneuron types

10.1101/735019 ◽

2019 ◽

Cited By ~ 3

Author(s):

Sean M. Kelly ◽

Ricardo Raudales ◽

Monika Moissidis ◽

Gukham Kim ◽

Z. Josh Huang

Keyword(s):

Radial Glia ◽

Large Set ◽

Cortical Interneuron ◽

Intermediate Progenitors ◽

Inhibitory Mechanisms ◽

Glial Progenitors ◽

Radial Glial ◽

Chandelier Cells ◽

Second Wave ◽

Inside Out

SUMMARYGABAergic interneurons deploy numerous inhibitory mechanisms that regulate cortical circuit operation, but the developmental programs that generate diverse interneuron types remain not well understood. We carried out a comprehensive genetic fate mapping of the radial glial progenitors (RGs) and intermediate progenitors (IP) in the medial ganglionic eminence (MGE). We reveal that Nkx2.1+ RGs are multipotent and mediate two consecutive waves of neurogenesis, each sequentially generating different sets of interneuron types that laminate the neocortex in an inside-out-inside order. The first wave is restricted to the caudal MGE, has limited neurogenic capacity, and involves mostly apical IPs. The second wave initiates throughout the MGE and features a large set of fate-restricted basal IPs that amplify and diversify interneurons. Chandelier cells are generated toward the end of each wave and laminate in an outside-in order. Therefore, separate pools of multipotent RGs deploy temporal cohorts of IPs to sequentially generate diverse interneuron types.

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An Early Developmental Marker for Radial Glia in Rat Spinal Cord

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162648 ◽

1996 ◽

Vol 54 ◽

pp. 36-37

Author(s):

V. Kriho ◽

H.-Y. Yang ◽

C.-M. Lue ◽

N. Lieska ◽

G. D. Pappas

Keyword(s):

Spinal Cord ◽

Intermediate Filament ◽

Radial Glia ◽

Rat Spinal Cord ◽

Future Studies ◽

Spinal Cord Development ◽

Median Septum ◽

Differentiation Marker ◽

Early Developmental ◽

Developing Rat

Radial glia have been classically defined as those early glial cells that radially span their thin processes from the ventricular to the pial surfaces in the developing central nervous system. These radial glia constitute a transient cell population, disappearing, for the most part, by the end of the period of neuronal migration. Traditionally, it has been difficult to definitively identify these cells because the principal criteria available were morphologic only.Using immunofluorescence microscopy, we have previously defined a phenotype for radial glia in rat spinal cord based upon the sequential expression of vimentin, glial fibrillary acidic protein and an intermediate filament-associated protein, IFAP-70/280kD. We report here the application of another intermediate filament-associated protein, IFAP-300kD, originally identified in BHK-21 cells, to the immunofluorescence study of radial glia in the developing rat spinal cord.Results showed that IFAP-300kD appeared very early in rat spinal cord development. In fact by embryonic day 13, IFAP-300kD immunoreactivity was already at its peak and was observed in most of the radial glia which span the spinal cord from the ventricular to the subpial surfaces (Fig. 1). Interestingly, from this time, IFAP-300kD immunoreactivity diminished rapidly in a dorsal to ventral manner, so that by embryonic day 16 it was detectable only in the maturing macroglial cells in the marginal zone of the spinal cord and the dorsal median septum (Fig. 2). By birth, the spinal cord was essentially immuno-negative for this IFAP. Thus, IFAP-300kD appears to be another differentiation marker available for future studies of gliogenesis, especially for the early stages of radial glia differentiation.

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