Dissection of genetic pathways critical for myelinating Schwann cell development

描述(申请人提供)：周围神经病是一组疾病，其特征是四肢运动功能受损和感觉丧失。一般人群中有2%-8%的人患有周围神经病变，这使得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患者携带编码对髓鞘雪旺细胞至关重要的蛋白质的基因突变。雪旺细胞是一种隔离周围神经轴突并为其提供营养因子的细胞群体。目前，我们对雪旺细胞发育和动态平衡所涉及的转录层次结构的了解非常有限。含SRY-box基因10(Sox10)编码一种转录因子，对雪旺细胞的发育和功能至关重要。重要的是，Sox10基因和受Sox10基因调控的基因突变与脱髓鞘周围神经病有关。因此，新的Sox10靶基因的识别和鉴定将为脱髓鞘周围神经病提供更多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)在全基因组范围内鉴定髓鞘雪旺细胞中的Sox10靶基因；(2)确定Sox10是否是髓鞘雪旺细胞中两个新的靶基因(SH3KBP1和BCAS3)表达所必需的；以及(3)鉴定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.