Characterization of Chd7 in central nervous system neural stem cells

描述（由申请人提供）：严格调控的基因表达对于发育和成人组织中神经干细胞的正常功能至关重要。通过表观遗传修饰的染色质状态的调制被提出来调节侧脑室的室管膜下区（SVZ）的神经发生，但所涉及的确切机制尚未确定。SVZ神经干细胞龛负责产生嗅球（OB）中间神经元，这些中间神经元在嗅觉记忆和嗅觉信号转导中发挥不可或缺的作用。虽然组蛋白修饰基因如Trithorax组成员Mll 1和Polycomb组成员Bmi 1已被鉴定为SVZ神经干细胞的有效调节剂，但染色质重塑在神经干细胞调节中的作用尚未确定。我们实验室先前的研究已经证明ATP依赖性染色质重塑酶CHD7对于嗅觉感觉上皮和内耳中的适当神经干细胞功能和神经发生是必需的。在人类中，CHD7的突变导致CHARGE综合征，这是一种影响眼睛，耳朵，鼻子和中枢神经系统（CNS）发育的多种先天性异常疾病。CHD7还与发育障碍有关，包括自闭症谱系障碍和卡尔曼综合征，其特征在于低促性腺功能减退症。chd7作为一个全球性的调节神经发生在脑室下区和感觉上皮细胞。对SVZ中Chd7的遗传靶点的更深入了解可能会发现调节神经发生的新机制，并有助于解释在CHARGE综合征和相关疾病中观察到的感觉和中枢神经系统缺陷的病因。我的总体假设是CHD7调节围产期和成人中枢神经系统神经干细胞的增殖，维持和神经发生。为了验证这一假设，我提出了以下具体目标：目的1：确定在体内Chd 7调节室管膜下区增殖和嗅球中间神经元的神经发生。目的2：明确Chd 7在室管膜下区神经干细胞自我更新和细胞命运特化中的作用。目标3：阐明CHD7与参与室管膜下区神经元分化和细胞周期维持的基因增强子元件的结合。

DESCRIPTION (provided by applicant): 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.