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The Doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1
- Publication Year :
- 2017
- Publisher :
- National Academy of Sciences, 2017.
-
Abstract
- The mechanisms that determine whether a neural progenitor cell (NPC) reenters the cell cycle or exits and differentiates are pivotal for generating cells in the correct numbers and diverse types, and thus 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 doublesex- and mab-3–related transcription factor a2 (Dmrta2, also known as Dmrt5) 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 postmitotic neurons of NPCs derived from embryonic stem cells and in Emx1-cre conditional mutant mice. Dmrta2 function is linked to the regulation of Hes1 and other proneural genes, as demonstrated by genome-wide RNA-seq and direct binding of Dmrta2 to the Hes1 genomic locus. Moreover, transient Hes1 expression rescues precocious neurogenesis in Dmrta2 knockout NPCs. Our study thus establishes a link between Dmrta2 modulation of Hes1 expression and the maintenance of NPCs during cortical development.
- Subjects :
- 0301 basic medicine
Neurogenesis
Doublesex
Proneural genes
Biology
Mice
03 medical and health sciences
Neural Stem Cells
otorhinolaryngologic diseases
Animals
Transgenes
HES1
Progenitor cell
Transcription factor
Embryonic Stem Cells
Cell Proliferation
Mice, Knockout
Neurons
Genetics
Multidisciplinary
Cell Cycle
Gene Expression Regulation, Developmental
Cell Differentiation
Cell cycle
Embryonic stem cell
Cell biology
Phenotype
030104 developmental biology
PNAS Plus
Transcription Factor HES-1
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....f240ae0c8fe3bfef43d90f538f60597f