Molecular and genetic analysis of sanpodo

描述（由申请人提供）：神经系统与其他组织的区别在于其细胞网络的复杂性。这种复杂性是建立在功能性神经系统中神经元的巨大多样性之上的。不对称细胞分裂，即一个前体细胞分裂产生两个具有不同命运的兄弟细胞，在产生脊椎动物和无脊椎动物神经系统中发现的细胞多样性中起着核心作用。对果蝇的研究已经开始阐明不对称分裂的遗传和分子基础。这些数据表明Notch信号通路与膜相关蛋白Numb相反，介导神经（和肌肉）前体的不对称分裂。目前的模型是，Numb在前体分裂成一个兄弟细胞的过程中不对称分离，在那里它阻断Notch信号并允许这个细胞采用ceb1命运。另一个兄弟姐妹，缺乏Numb蛋白，接受活跃的Notch输入，并采用cea1细胞命运。通过这种方式，Notch/Numb盒体介导了大多数（如果不是全部的话）兄弟中枢神经系统神经元的二元细胞命运选择。通过基因筛选，我们发现sanpodo是一个与Notch通路一起介导不对称分裂的基因，sanpodo最初被认为是编码F-actin/原肌球蛋白结合蛋白Tropomodulin的脊椎动物基因的同源基因。然而，我们的数据提供了令人信服的证据，证明三坡多并不编码Tropomodulin，而是一种新的四通跨膜蛋白。这一建议的目标是阐明遗传和分子基础，通过三坡多介导不对称分裂。具体而言，我们建议：(1)确认三坡渡的分子身份；(2)完成三足病的系统遗传、表达和分子分析；(3)通过鉴定sanpodo相互作用蛋白，阐明sanpodo调控不对称分裂的分子机制。哺乳动物中存在Notch通路成员和numb的同源物。最近的遗传、表达和分子研究表明，这些因素也调节着哺乳动物的不对称分裂。因此，阐明Sanpodo功能如何与Notch和Numb功能结合以调节不对称细胞分裂，可能为在动物发育过程中创造细胞多样性的分子和遗传机制提供一般见解。

DESCRIPTION (provided by applicant): The feature that sets the nervous system apart from other tissues is the complexity of its cell network. This complexity is founded on the great diversity of neurons that populate a functional nervous system. Asymmetric cell divisions, in which a precursor cell divides to produce two sibling cells of distinct fates, play a central role in generating the cellular diversity found in both vertebrate and invertebrate nervous systems. Research in Drosophila has begun to elucidate the genetic and molecular basis of asymmetric divisions. These data indicate that the Notch signaling pathway acts in opposition to the membrane-associated protein Numb to mediate the asymmetric division of neural (and muscle) precursors. The present model is that Numb is asymmetrically segregated during precursor division into one sibling where it blocks Notch signaling and allows this cell to adopt the CEB1fate. The other sibling, which lacks Numb protein, receives active Notch input and adopts the CEA1cell fate. In this manner, the Notch/Numb cassette mediates the binary cell fate choice of most if not all sibling CNS neurons. Through a genetic screen we identified sanpodo as a gene that acts with the Notch pathway to mediate asymmetric divisions, sanpodo was initially characterized as the homolog of the vertebrate gene encoding the F-actin/tropomyosin binding protein, Tropomodulin. However, our data provide compelling evidence that sanpodo does not encode Tropomodulin but rather a novel four-pass transmembrane protein. The goals of this proposal are to elucidate the genetic and molecular basis through which sanpodo mediates asymmetric divisions. Specifically, we propose: (1) to confirm the molecular identity of sanpodo; (2) to complete a systematic genetic, expression and molecular analysis of sanpodo; and (3) to elucidate the molecular mechanism by which sanpodo regulates asymmetric divisions by identifying Sanpodo-interacting proteins. Mammalian homologs of Notch pathway members and numb exist. Recent genetic, expression and molecular studies suggest these factors also regulate asymmetric divisions in mammals. Thus, the elucidation of how Sanpodo function integrates with that of Notch and Numb to regulate asymmetric cell divisions is likely to provide general insights into the molecular and genetic mechanisms that create cell diversity throughout animal development.