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

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 centrosom...

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Autores principales: Bendriem, Raphael M, Singh, Shawn, Aleem, Alice Abdel, Antonetti, David A, Ross, M Elizabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890460/
https://www.ncbi.nlm.nih.gov/pubmed/31794381
http://dx.doi.org/10.7554/eLife.49376
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author Bendriem, Raphael M
Singh, Shawn
Aleem, Alice Abdel
Antonetti, David A
Ross, M Elizabeth
author_facet Bendriem, Raphael M
Singh, Shawn
Aleem, Alice Abdel
Antonetti, David A
Ross, M Elizabeth
author_sort Bendriem, Raphael M
collection PubMed
description 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.
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spelling pubmed-68904602019-12-06 Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex Bendriem, Raphael M Singh, Shawn Aleem, Alice Abdel Antonetti, David A Ross, M Elizabeth eLife Human Biology and Medicine 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. eLife Sciences Publications, Ltd 2019-12-03 /pmc/articles/PMC6890460/ /pubmed/31794381 http://dx.doi.org/10.7554/eLife.49376 Text en © 2019, Bendriem et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Human Biology and Medicine
Bendriem, Raphael M
Singh, Shawn
Aleem, Alice Abdel
Antonetti, David A
Ross, M Elizabeth
Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex
title Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex
title_full Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex
title_fullStr Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex
title_full_unstemmed Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex
title_short Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex
title_sort tight junction protein occludin regulates progenitor self-renewal and survival in developing cortex
topic Human Biology and Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890460/
https://www.ncbi.nlm.nih.gov/pubmed/31794381
http://dx.doi.org/10.7554/eLife.49376
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