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Elife. 2019 Dec 3;8. pii: e49376. doi: 10.7554/eLife.49376.

Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex.

Author information

1
Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States.
2
Graduate School of Medical Sciences, Weill Cornell Medicine, New York, United States.
3
Weill Cornell Medicine Qatar, Doha, Qatar.
4
Kellogg Eye Center, Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, United States.

Abstract

Occludin (OCLN) mutations cause human microcephaly and cortical malformation. A tight junction component thought absent in neuroepithelium after neural tube closure, OCLN isoform-specific expression extends into corticogenesis. Full-length and truncated isoforms localize to neuroprogenitor centrosomes, but full-length OCLN transiently localizes to plasma membranes while only truncated OCLN continues at centrosomes throughout neurogenesis. Mimicking human mutations, full-length OCLN depletion in mouse and in human CRISPR/Cas9-edited organoids produce early neuronal differentiation, reduced progenitor self-renewal and increased apoptosis. Human neural progenitors were more severely affected, especially outer radial glial cells, which mouse embryonic cortex lacks. Rodent and human mutant progenitors displayed reduced proliferation and prolonged M-phase. OCLN interacted with mitotic spindle regulators, NuMA and RAN, while full-length OCLN loss impaired spindle pole morphology, astral and mitotic microtubule integrity. Thus, early corticogenesis requires full-length OCLN to regulate centrosome organization and dynamics, revealing a novel role for this tight junction protein in early brain development.

KEYWORDS:

OCLN; brain malformation; centrosome regulation; cortical neurogenesis; human; human biology; medicine; microcephaly; mouse; neuroscience; tight junction protein

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