The Doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1

Young, Fraser I., Keruzore, Marc, Nan, Xinsheng ORCID: https://orcid.org/0000-0002-0865-7934, Gennet, Nicole, Bellefroid, Eric J. and Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643 2017. The Doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1. Proceedings of the National Academy of Sciences 114 (28) , E5599-E5607. 10.1073/pnas.1705186114

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Abstract

The mechanisms that determine whether a neural progenitor cell (NPC) re-enters the cell cycle or exits and differentiates are pivotal for generating cells in correct numbers and diverse types, and hence dictate proper brain development. Combining gain-of-function and loss-of-function approaches in an embryonic stem cell-derived cortical differentiation model, we report that Dmrta2 plays an important role in maintaining NPCs in the cell cycle. Temporally controlled expression of transgenic Dmrta2 in NPCs suppresses differentiation without affecting their neurogenic competence. In contrast, Dmrta2 knockout accelerates the cell cycle exit and differentiation into post-mitotic neurons of NPCs derived from embryonic stem cells and in Emx1-cre conditional mutant mice. Dmrta2 function was linked to the regulation of Hes1 and other proneural genes as demonstrated by genome wide RNAseq and direct binding of Dmrta2 to the Hes1 genomic locus. Moreover, transient Hes1 expression rescues precocious neurogenesis in Dmrta2 knockout NPCs. Our study therefore establishes a novel link between Dmrta2 modulation of Hes1 expression and the maintenance of NPCs during cortical development. \

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Uncontrolled Keywords:	Dmrta2, Hes1, cell cycle, transcription factor, neurogenesis,
Additional Information:	Freely available online through the PNAS open access option
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	9 June 2017
Date of Acceptance:	16 May 2017
Last Modified:	29 Jun 2023 17:37
URI:	https://orca.cardiff.ac.uk/id/eprint/101329

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