Semaphorin 6A–Plexin A2/A4 Interactions with Radial Glia Regulate Migration Termination of Superficial Layer Cortical Neurons

Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase-activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP-knockdown (KD) mouse model created by retroviral insertion of a LacZ-encoding gene-trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunohistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. Bromodeoxyuridine birth dating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II-IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP-KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition from multipolar to bipolar morphology in migrating postmitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of the cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP-KD brains. We found that Dab2IP-KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a subpopulation of later-born (layers II-IV) neurons, likely through the regulation of Rap1 and integrin signaling.

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Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

Development ◽

10.1242/dev.187526 ◽

2020 ◽

Vol 147 (22) ◽

pp. dev187526

Author(s):

Miguel Turrero García ◽

José-Manuel Baizabal ◽

Diana N. Tran ◽

Rui Peixoto ◽

Wengang Wang ◽

...

Keyword(s):

Cortical Neurons ◽

Radial Glia ◽

Regulatory Elements ◽

Neural Progenitors ◽

Gabaergic Interneuron ◽

Gabaergic Interneurons ◽

Proliferative Capacity ◽

Medial Ganglionic Eminence ◽

Developmental Gene Expression ◽

Dorsal Telencephalon

ABSTRACTThe mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from the dorsal telencephalon, whereas inhibitory interneurons are generated in its ventral portion. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear whether PRDM16 plays a similar role in neurogenesis in both dorsal and ventral progenitor lineages and, if so, whether it regulates common or unique networks of genes. Here, we show that Prdm16 expression in mouse medial ganglionic eminence (MGE) progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of forebrain GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. PRDM16 regulates convergent developmental gene expression programs in the cortex and MGE, which utilize both common and region-specific sets of genes to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

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Human Pluripotent Stem Cell-Derived Radial Glia Recapitulate Developmental Events and Provide Real-Time Access to Cortical Neurons and Astrocytes

Stem Cells Translational Medicine ◽

10.5966/sctm.2014-0137 ◽

2015 ◽

Vol 4 (5) ◽

pp. 437-447 ◽

Cited By ~ 11

Author(s):

Lishu Duan ◽

Chian-Yu Peng ◽

Liuliu Pan ◽

John A. Kessler

Keyword(s):

Stem Cell ◽

Real Time ◽

Cortical Neurons ◽

Pluripotent Stem Cell ◽

Radial Glia ◽

Human Pluripotent Stem Cell

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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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Gα12/Gα13 Deficiency Causes Localized Overmigration of Neurons in the Developing Cerebral and Cerebellar Cortices

Molecular and Cellular Biology ◽

10.1128/mcb.00651-07 ◽

2007 ◽

Vol 28 (5) ◽

pp. 1480-1488 ◽

Cited By ~ 47

Author(s):

Alexandra Moers ◽

Alexander Nürnberg ◽

Sandra Goebbels ◽

Nina Wettschureck ◽

Stefan Offermanns

Keyword(s):

G Protein ◽

Purkinje Cells ◽

Cortical Neurons ◽

Radial Glia ◽

G Protein Coupled Receptors ◽

Cortical Plate ◽

Genes Encoding ◽

Sphingosine 1 Phosphate ◽

Cerebellar Purkinje Cells ◽

G Protein Coupled

ABSTRACT The heterotrimeric G proteins G12 and G13 link G-protein-coupled receptors to the regulation of the actin cytoskeleton and the induction of actomyosin-based cellular contractility. Here we show that conditional ablation of the genes encoding the α-subunits of G12 and G13 in the nervous system results in neuronal ectopia of the cerebral and cerebellar cortices due to overmigration of cortical plate neurons and cerebellar Purkinje cells, respectively. The organization of the radial glia and the basal lamina was not disturbed, and the Cajal-Retzius cell layer had formed normally in mutant mice. Embryonic cortical neurons lacking G12/G13 were unable to retract their neurites in response to lysophosphatidic acid and sphingosine-1-phosphate, indicating that they had lost the ability to respond to repulsive mediators acting via G-protein-coupled receptors. Our data indicate that G12/G13-coupled receptors mediate stop signals and are required for the proper positioning of migrating cortical plate neurons and Purkinje cells during development.

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Human Cortical Neurons Originate from Radial Glia and Neuron-Restricted Progenitors

Journal of Neuroscience ◽

10.1523/jneurosci.0111-07.2007 ◽

2007 ◽

Vol 27 (15) ◽

pp. 4132-4145 ◽

Cited By ~ 81

Author(s):

Z. Mo ◽

A. R. Moore ◽

R. Filipovic ◽

Y. Ogawa ◽

I. Kazuhiro ◽

...

Keyword(s):

Cortical Neurons ◽

Radial Glia

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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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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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Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

10.1101/2019.12.17.879510 ◽

2019 ◽

Author(s):

Miguel Turrero García ◽

José-Manuel Baizabal ◽

Diana Tran ◽

Rui Peixoto ◽

Wengang Wang ◽

...

Keyword(s):

Cortical Neurons ◽

Radial Glia ◽

Regulatory Elements ◽

Neural Progenitors ◽

Gabaergic Interneuron ◽

Gabaergic Interneurons ◽

Proliferative Capacity ◽

Cortical Circuits ◽

Developmental Gene Expression ◽

Dorsal Telencephalon

SUMMARYThe mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from progenitors located in the dorsal telencephalon, while inhibitory interneurons are generated by ventral telencephalic progenitors. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear if PRDM16 functions plays a role in neurogenesis in both dorsal and ventral progenitor lineages, and if so, whether it does so by regulating common or unique networks of genes. Here, we show that Prdm16 expression in MGE progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of pallial GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. Our results highlight the importance of PRDM16 for the development of both excitatory and inhibitory cortical circuits. We demonstrate the existence of convergent developmental gene expression programs regulated by PRDM16, which utilize both common and region-specific sets of genes in the cortex and the MGE to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

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