Dissection of genetic pathways critical for myelinating Schwann cell development

描述（由申请人提供）：周围神经病是一组以四肢运动功能受损和感觉丧失为特征的疾病。2-8%的普通人群受到周围神经病变的影响，使这些疾病成为重要的公共卫生问题。超过80%的遗传性周围神经病患者携带编码髓鞘形成雪旺细胞关键蛋白质的基因突变，雪旺细胞是一种隔离周围神经轴突并为周围神经轴突提供营养因子的细胞群。目前，我们有一个非常有限的了解，在雪旺细胞的发展和稳态的转录层次。含SRY盒基因10（SOX 10）编码一种对雪旺细胞发育和功能至关重要的转录因子。重要的是，SOX 10和由SOX 10调节的基因座中的突变与脱髓鞘性周围神经病变有关。因此，新的SOX 10靶基因座的鉴定和表征将为脱髓鞘周围神经病提供额外的候选基因和关于雪旺细胞生物学的关键知识。为此，我们将：（1）在髓鞘形成的许旺细胞中进行SOX 10靶基因座的全基因组鉴定;（2）确定SOX 10是否是两个新靶基因（SH 3 KBP 1和BCAS 3）在髓鞘形成的许旺细胞中表达所必需的;和（3）表征SH 3 KBP 1和BCAS 3在髓鞘形成的许旺细胞中的功能。 公共卫生相关性：雪旺氏细胞是周围神经的重要组成部分，周围神经是手和脚的运动和感觉所必需的结构。关于许旺细胞中的基因调控知之甚少。该提案的主要目标是通过全基因组鉴定雪旺细胞中表达的新基因和蛋白质并确定它们如何促进雪旺细胞功能来解决这种知识的缺乏。这些研究将提供有关周围神经功能和相关人类疾病（如周围神经病变和多发性硬化症）的关键信息。

DESCRIPTION (provided by applicant): Peripheral neuropathies are a group of diseases characterized by impaired motor function and sensory loss in the extremities. Between 2-8% of the general population is affected with a peripheral neuropathy, making these diseases a significant public health concern. More than 80% of patients with inherited peripheral neuropathy carry mutations in genes encoding proteins critical for myelinating Schwann cells-a cell population that insulates and provides trophic factors to peripheral nerve axons. Currently, we have a very limited understanding of the transcriptional hierarchies involved in Schwann cell development and homeostasis. The SRY-box containing gene 10 (SOX10) encodes a transcription factor that is essential for Schwann cell development and function. Importantly, mutations in SOX10 and in loci regulated by SOX10 have been implicated in demyelinating peripheral neuropathies. Thus, the identification and characterization of novel SOX10 target loci will provide additional candidate genes for demyelinating peripheral neuropathies and key knowledge regarding Schwann cell biology. Toward this, we will: (1) Perform genome-wide identification of SOX10 target loci in myelinating Schwann cells; (2) Determine if SOX10 is necessary for the expression of two novel target genes (SH3KBP1 and BCAS3) in myelinating Schwann cells; and (3) Characterize the function of SH3KBP1 and BCAS3 in myelinating Schwann cells. PUBLIC HEALTH RELEVANCE: Schwann cells are a critical component of peripheral nerves-structures essential for mobility and sensation in the hands and feet. Remarkably little is known about gene regulation in Schwann cells. The major goal of this proposal is to address this lack of knowledge through genome-wide identification of novel genes and proteins expressed in Schwann cells and determining how they contribute to Schwann cell function. These studies will provide key information on the function of peripheral nerves and associated human diseases such as peripheral neuropathy and multiple sclerosis.