Tightly regulated gene expression is essential for the proper function of neural stem cells in developing and adult tissues. Modulation of chromatin states through epigenetic modifications is proposed to regulate neurogenesis in the subventricular zone (SVZ) of the lateral ventricle, but the precise mechanisms involved are not defined. The SVZ neural stem cell niche is responsible for producing olfactory bulb (OB) interneurons that play an integral role in olfactory memory and olfactory signal transduction. While histone modifying genes such as the Trithorax-group member Mll1 and the Polycomb-group member Bmi1 have been identified as potent regulators of SVZ neural stem cells, the contribution of chromatin remodeling in neural stem cell regulation has not been established. Previous studies in our laboratory have demonstrated that the ATP- dependent chromatin remodeling enzyme CHD7 is essential for proper neural stem cell function and neurogenesis in the olfactory sensory epithelium and inner ear. In humans, mutations in CHD7 cause CHARGE Syndrome, a multiple congenital anomaly disorder that affects development of the eyes, ears, nose, and central nervous system (CNS). CHD7 has also been linked to developmental disorders including autism spectrum disorder and Kallmann Syndrome, which is characterized by hypogondotropic hypogonadism. Chd7 is emerging as a global regulator of neurogenesis in both the subventricular zone and in sensory epithelia. A more thorough understanding of genetic targets for Chd7 in the SVZ may uncover novel mechanisms regulating neurogenesis, and help explain the etiologies of sensory and central nervous system defects observed in CHARGE Syndrome and related disorders. My global hypothesis is that CHD7 regulates proliferation, maintenance and neurogenesis of perinatal and adult central nervous system neural stem cells. To test this hypothesis, I propose the following specific aims:
Aim 1 : Determine the in vivo Chd7 regulation of subventricular zone proliferation and neurogenesis of olfactory bulb interneurons.
Aim 2 : Define the in vitro role of Chd7 in the self-renewal and cell fate specification of subventricular zone neural stem cells.
Aim 3 : Elucidate CHD7 binding to enhancer elements of genes involved in neuronal differentiation and cell cycle maintenance in the subventricular zone.
This project will greatly enhance our fundamental knowledge of CHD7 function in mammalian central nervous system development and maintenance. Recruitment of histone modifying and chromatin remodeling enzymes to genes involved in stem cell maintenance and neurogenesis is likely to be essential for the development and homeostasis of neural stem cell niches and sensory tissues. These data may aid in the production of diagnostics and therapeutics for neural sensory impairment and related disorders.
|Micucci, Joseph A; Layman, Wanda S; Hurd, Elizabeth A et al. (2014) CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome. Hum Mol Genet 23:434-48|