The Role of ATP-dependent Chromatin Remodeling Enzyme CHD7 in the Development and Maintenance of Murine Neural Stem Cells.

[摘要] Cell type-specific gene expression is a tightly controlled process which is facilitated by several classes of proteins including transcription factors, histone modifying enzymes and ATP-dependent chromatin remodeling enzymes.The CHD class of chromatin remodelers is important for development and maintenance of mammalian stem cell populations and their progeny.In humans, haploinsufficiency for the CHD family member CHD7 results in a multiple congenital anomaly disorder called CHARGE syndrome.Defects of the eye, ear, heart, brain, olfactory organs and craniofacial features are commonly observed in CHARGE syndrome.Notably, CHARGE individuals display decreased or absent sense of smell (hyposmia or anosmia) and small or absent olfactory bulbs (OB) and tracts (arrhinencephaly).The OB is populated by neurons born in a neural stem cell niche located along the lateral walls of the lateral ventricles in a region termed the subventricular zone (SVZ).The process of neuronal migration from the SVZ to the OB begins during late embryogenesis and continues into adulthood, implying that CHD7 deficiency in the SVZ neural stem cell niche may play a role in the olfaction.In order to study the role of CHD7 in SVZ neural stem cell function, I generated conditional Chd7 knockout mice using a Chd7flox allele and ubiquitous or neural stem cell-specific Cre recombinases.In adult mice, Chd7 deficiency leads to decreased SVZ proliferation, ventriculomegaly, fewer neuroblasts and mature OB interneurons, and increased glial cells.Conditional adult and perinatal knockout mice display defects in proliferation, self-renewal and neuronal differentiation which can be rescued by modulation of retinoic acid signaling.By chromatin immunoprecipitation, CHD7 binds to the promoters of retinoic acid receptors and pro-neural genes in neural stem cells.Additionally, microarray analysis of SVZ gene expression from control and Chd7 conditional knockout mice shows that neuronal differentiation, migration and maturation genes are down-regulated upon loss of Chd7.Together, these data suggest that CHD7 plays a critical role in the development and maintenance of the SVZ neural stem cell niche.My research has helped to identify molecular mechanisms of CHD7 function in neural stem cells could improve diagnostic and therapeutic approaches for individuals with CHARGE syndrome and related disorders.

[发布机构] University of Michigan

[效力级别] Epigenetics

[关键词] Neural Stem Cells;Epigenetics;Brain Development;Mouse Models of Human Disease;Biological Chemistry;Science;Biological Chemistry