Abstract
Olig2 is indispensable for motoneuron and oligodendrocyte fate-specification in the pMN domain of embryonic spinal cords, and also involved in the proliferation and differentiation of several cell types in the nervous system, including neural progenitor cells (NPCs) and oligodendrocytes. However, how Olig2 controls these diverse biological processes remains unclear. Here, we demonstrated that a novel Olig2-binding protein, DEAD-box helicase 20 (Ddx20), is indispensable for the survival of NPCs and oligodendrocyte progenitor cells (OPCs). A central nervous system (CNS)-specific Ddx20 conditional knockout (cKO) demonstrated apoptosis and cell cycle arrest in NPCs and OPCs, through the potentiation of the p53 pathway in DNA damage-dependent and independent manners, including SMN complex disruption and the abnormal splicing of Mdm2 mRNA. Analyzes of Olig2 null NPCs showed that Olig2 contributed to NPC proliferation through Ddx20 protein stabilization. Our findings provide novel mechanisms underlying the Olig2-mediated proliferation of NPCs, via the Ddx20-p53 axis, in the embryonic CNS.
Highlights
During neural development, neuroepithelial cell fate is determined by region-specific transcription factors, the expression of which is regulated by morphogens, resulting in various types of neurons and glial cells being generated in a region-specific manner [1]
Co-immunoprecipitation analysis, using tagged proteins expressed in HEK293 cells, demonstrated an interaction between Oligodendrocyte transcription factor 2 (Olig2) and DEAD-box helicase 20 (Ddx20), but no interaction was observed between Olig2 and a C-terminal-truncated form of Ddx20 (Fig. 1B)
The interaction between endogenous Olig2 and Ddx20 was confirmed in cultured neural progenitor cells (NPCs), derived from embryonic mouse telencephalons (Fig. 1C)
Summary
Neuroepithelial cell fate is determined by region-specific transcription factors, the expression of which is regulated by morphogens, resulting in various types of neurons and glial cells being generated in a region-specific manner [1]. Olig is expressed in the ventral ventricular zone (VZ), termed pMN domain, where oligodendrocyte progenitor cells (OPCs) are produced. Several studies, both in vivo and in vitro, have demonstrated that Olig regulates motor neurons and OPC production from the pMN domain [2,3,4] and the neural progenitor cell (NPC) proliferation [5] and oligodendrocyte differentiation from OPCs [6]. How Olig controls these diverse biological processes remains largely unknown
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