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

TitleTight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex.
Publication TypeJournal Article
Year of Publication2019
AuthorsBendriem RM, Singh S, Aleem AAbdel, Antonetti DA, M Ross E
JournalElife
Volume8
Date Published2019 Dec 03
ISSN2050-084X
Abstract

() 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.

DOI10.7554/eLife.49376
Alternate JournalElife
PubMed ID31794381
Grant ListP01HD067244 / NH / NIH HHS / United States
R01NS105477 / NH / NIH HHS / United States
Training Fellowship (T32HD060600) / NH / NIH HHS / United States