Periventricular Heterotopia: Shuttling of Proteins through Vesicles and Actin in Cortical Development and Disease

During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone. Vesicle trafficking is also required for maintenance of lipid and protein cycling within the leading and trailing edge of migratory neurons, as well as dendrites and synapses of mature neurons. Defects in this transport machinery disrupt neuronal identity, migration, and connectivity and give rise to a malformation of cortical development termed as periventricular heterotopia (PH). PH is characterized by a reduction in brain size, ectopic clusters of neurons localized along the lateral ventricle, and epilepsy and dyslexia. These anatomical anomalies correlate with developmental impairments in neural progenitor proliferation and specification, migration from loss of neuroependymal integrity and neuronal motility, and aberrant neuronal process extension. Genes causal for PH regulate vesicle-mediated endocytosis along an actin cytoskeletal network. This paper explores the role of these dynamic processes in cortical development and disease.

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Loss of PP2A Disrupts the Retention of Radial Glial Progenitors in the Telencephalic Niche to Impair the Generation for Late-Born Neurons During Cortical Development†

Cerebral Cortex ◽

10.1093/cercor/bhaa042 ◽

2020 ◽

Vol 30 (7) ◽

pp. 4183-4196

Author(s):

Chaoli Huang ◽

Tingting Liu ◽

Qihui Wang ◽

Weikang Hou ◽

Cuihua Zhou ◽

...

Keyword(s):

Neural Progenitor Cells ◽

Ventricular Zone ◽

Cortical Development ◽

Underlying Mechanism ◽

Conditional Knockout ◽

Glial Progenitors ◽

Radial Glial ◽

Vitro Analysis ◽

The Impact

Abstract Telencephalic radial glial progenitors (RGPs) are retained in the ventricular zone (VZ), the niche for neural stem cells during cortical development. However, the underlying mechanism is not well understood. To study whether protein phosphatase 2A (PP2A) may regulate the above process, we generate Ppp2cα conditional knockout (cKO) mice, in which PP2A catalytic subunit α (PP2Acα) is inactivated in neural progenitor cells in the dorsal telencephalon. We show that RGPs are ectopically distributed in cortical areas outside of the VZ in Ppp2cα cKO embryos. Whereas deletion of PP2Acα does not affect the proliferation of RGPs, it significantly impairs the generation of late-born neurons. We find complete loss of apical adherens junctions (AJs) in the ventricular membrane in Ppp2cα cKO cortices. We observe abundant colocalization for N-cadherin and PP2Acα in control AJs. Moreover, in vitro analysis reveals direct interactions of N-cadherin to PP2Acα and to β-catenin. Overall, this study not only uncovers a novel function of PP2Acα in retaining RGPs into the VZ but also demonstrates the impact of PP2A-dependent retention of RGPs on the generation for late-born neurons.

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ATF5 deficiency causes abnormal cortical development

Scientific Reports ◽

10.1038/s41598-021-86442-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mariko Umemura ◽

Yasuyuki Kaneko ◽

Ryoko Tanabe ◽

Yuji Takahashi

Keyword(s):

Cerebral Cortex ◽

Glial Cells ◽

Leucine Zipper ◽

Ventricular Zone ◽

Cortical Development ◽

Physiological Role ◽

Basic Leucine Zipper ◽

Radial Glial Cells ◽

Radial Migration ◽

Radial Glial

AbstractActivating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors. We previously reported that ATF5-deficient (ATF5−/−) mice exhibited behavioural abnormalities, including abnormal social interactions, reduced behavioural flexibility, increased anxiety-like behaviours, and hyperactivity in novel environments. ATF5−/− mice may therefore be a useful animal model for psychiatric disorders. ATF5 is highly expressed in the ventricular zone and subventricular zone during cortical development, but its physiological role in higher-order brain structures remains unknown. To investigate the cause of abnormal behaviours exhibited by ATF5−/− mice, we analysed the embryonic cerebral cortex of ATF5−/− mice. The ATF5−/− embryonic cerebral cortex was slightly thinner and had reduced numbers of radial glial cells and neural progenitor cells, compared to a wild-type cerebral cortex. ATF5 deficiency also affected the basal processes of radial glial cells, which serve as a scaffold for radial migration during cortical development. Further, the radial migration of cortical upper layer neurons was impaired in ATF5−/− mice. These results suggest that ATF5 deficiency affects cortical development and radial migration, which may partly contribute to the observed abnormal behaviours.

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Lis1 and Ndel1 influence the timing of nuclear envelope breakdown in neural stem cells

The Journal of Cell Biology ◽

10.1083/jcb.200803071 ◽

2008 ◽

Vol 182 (6) ◽

pp. 1063-1071 ◽

Cited By ~ 58

Author(s):

Sachin Hebbar ◽

Mariano T. Mesngon ◽

Aimee M. Guillotte ◽

Bhavim Desai ◽

Ramses Ayala ◽

...

Keyword(s):

Nuclear Envelope ◽

Cell Fate ◽

Ventricular Zone ◽

Mitotic Cell ◽

Cytoplasmic Dynein ◽

Developmental Defects ◽

Animal Development ◽

Cell Fate Decisions ◽

Nuclear Envelope Breakdown ◽

Neural Cell Fate

Lis1 and Ndel1 are essential for animal development. They interact directly with one another and with cytoplasmic dynein. The developing brain is especially sensitive to reduced Lis1 or Ndel1 levels, as both proteins influence spindle orientation, neural cell fate decisions, and neuronal migration. We report here that Lis1 and Ndel1 reduction in a mitotic cell line impairs prophase nuclear envelope (NE) invagination (PNEI). This dynein-dependent process facilitates NE breakdown (NEBD) and occurs before the establishment of the bipolar spindle. Ndel1 phosphorylation is important for this function, regulating binding to both Lis1 and dynein. Prophase cells in the ventricular zone (VZ) of embryonic day 13.5 Lis1+/− mouse brains show reduced PNEI, and the ratio of prophase to prometaphase cells is increased, suggesting an NEBD delay. Moreover, prophase cells in the VZ contain elevated levels of Ndel1 phosphorylated at a key cdk5 site. Our data suggest that a delay in NEBD in the VZ could contribute to developmental defects associated with Lis1–Ndel1 disruption.

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