Dissection of genetic pathways critical for myelinating Schwann cell development

描述（由申请人提供）：周围神经病变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%的普通人群患有周围神经病变，使这些疾病成为一个重大的公共卫生问题。超过80%的遗传性周围神经病变患者携带编码髓鞘雪旺细胞（一种隔离并向周围神经轴突提供营养因子的细胞群）关键蛋白的基因突变。目前，我们对参与雪旺细胞发育和稳态的转录层次的了解非常有限。含有基因10 （SOX10）的SRY-box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，SOX10和由SOX10调控的基因座的突变与脱髓鞘周围神经病变有关。因此，新的SOX10靶位点的鉴定和表征将为脱髓鞘周围神经病变提供额外的候选基因，并为雪旺细胞生物学提供关键知识。为此，我们将：(1)在髓鞘化雪旺细胞中进行SOX10靶位点的全基因组鉴定；(2)确定在髓鞘雪旺细胞中两个新的靶基因（SH3KBP1和BCAS3）的表达是否需要SOX10；(3)表征SH3KBP1和BCAS3在髓鞘雪旺细胞中的功能。

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.