CHD2Directs The Proliferation And Differentiation Of Neural Progenitor Cells In The Developing Cerebral Cortex

The study of chromatin dynamics in eukaryotes has being an increasingly important topic in biology research especially in developmental biology.A large number of adenosine triphosphate (ATP)-dependent chromatin-remodeling complexes have been discovered that are responsible for chromosome dynamics, either globally or specifically at particular gene promoters. Based on chromatin dynamics,eukaryotes regulate gene expression.The CHD (Chromodomain Helicase DNA Binding Protein) family of proteins are defined by the presence of functional domains such as chromodomains(chromatin organization modifier), SNF2-related helicase/ATPase domains, specific DNA-binding domain.The CHD proteins are known to be involved in regulation of chromatin structure and gene transcription. CHD2belongs to the CHD subfamily I and has been associated with mammalian development, tumor suppression and DNA damage responses. CHD2is implicated in epileptic encephalopathies, growth retardation, lordokyphosis, mental retardation.During cortical development, neural progenitor cells(NPCs) are responsible for generating the diverse types of neurons and glial cells that intergrate and build the nervous system.As the ATP-dependent chromatin-remodeling complexe, the role of CHD2in the developing cerebral cortex remains unclear. In this study,we examined CHD2localization and show for the first time that it was exclusively localized to the nucleus in neural progenitors(NPCs).Thus it is suggestive of that CHD2is involved in self-renewing of NSCs. CHD2knockdown leaded to promote the differentiation of neural progenitor cells and inhibit their self-renewal in vitro experiments.In addition, to identify CHD2that regulates the differentiation of neural progenitor cells in the developing cerebral cortex, in utero electroporation was first applied that allow the neuronal differentiation of neural progenitor cells to be examined in vivo. In this regard, we investigated how CHD2regulated neurogenesis during cortical development.Knock down and overexpression experiments of CHD2specificity in neural progenitor cells of the E13.5d suggest the levels of CHD2expression are crucial for the regulation of neural progenitor cell proliferation.Knockdown of CHD2expression resulted in GFP labeled cells of VZ/SVZ (ventricular zone/subvertricular zone) significantly reduced. Moreover,BrdU-incorporated experiments confirmed that CHD2increased production of neural progenitor cells in S phase.Knockdown and overexpression of CHD2in the neural progenitor cells, their decreasing S-phase number during development is reflected by BrdU labeled cells in VZ/SVZ for knockdown of CHD2expression,And for overexpression of CHD2,the S-phase number is increased.To the end, We found CHD2binding the promoters of REST by ChIP (chromatin immunoprecipitation),thus CHD2directly regulates the transcription of REST (RE1-silencing transcription factor) to regulate the proliferation and differentiation of neural progenitor cells. In addition, CHD2combining CDS downstream of promoter region to regulate pluripotency in neural precursor cells possibly through other mechanisms.