Document Type

Article

Publication Date

8-22-2024

Identifier

DOI: 10.1038/s41467-024-51310-z; PMCID: PMC11341845

Abstract

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Journal Title

Nat Commun

Volume

15

Issue

1

First Page

7239

Last Page

7239

MeSH Keywords

Neural Stem Cells; Humans; Animals; Cell Division; Induced Pluripotent Stem Cells; Mice; Neurogenesis; Male; Female; Membrane Proteins; Guanine Nucleotide Exchange Factors; Disease Models, Animal; Cell Polarity

Keywords

Neural Stem Cells; Cell Division; Induced Pluripotent Stem Cells; Mice; Neurogenesis; Membrane Proteins; Guanine Nucleotide Exchange Factors; Animal Disease Models; Cell Polarity

Comments

Grants and funding

This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Publisher's Link: https://www.nature.com/articles/s41467-024-51310-z

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