Molecular Genetics of Stem Cell in Drosophila

描述（由申请人提供）：在高等真核生物中，某些组织由一种称为干细胞的特殊类型的细胞组成。干细胞分裂自我更新，同时产生一个致力于分化途径的后代。尽管干细胞非常重要，但我们对干细胞如何获得其特性或如何发挥其功能所知甚少。在果蝇中，原代神经前体细胞（neuroblast， NB）具有干细胞的功能，并通过自我更新的不对称有丝分裂进行分裂。在神经发生过程中，NB自我更新并产生神经节母细胞链（GMCs）。GMC是双电位的，它不自我更新，但不对称分裂产生两个不同的有丝分裂后神经元。因此，在给定的半节中，从-30个NBs中产生-320个不同的神经元。这表明，NBs作为干细胞的能力以及NBs和gmc通过不对称有丝分裂进行分裂的能力对于从少数前体细胞中产生大量神经元至关重要。我们的长期目标是利用果蝇中枢神经系统作为我们的模型系统，探索自我更新的干细胞类型的不对称分裂的遗传调控。为了研究自我更新和末端不对称分裂的问题，我们选择了几个不同的中枢神经系统谱系：MP2， NB7-3, GMC-1->RP2/sib和GMC-1->aCC/pCC。在过去的几年里，我们已经通过基因筛选在一个或多个谱系中发现了显示自我更新和终端不对称分裂的突变。在这项资助中，我们建议进一步研究这些突变。因此，我们的具体目标包括：(1)研究Midline在抑制神经前体细胞自我更新的不对称分裂电位中的作用；(2)确定neuralizedlike如何抑制前体细胞自我更新的不对称分裂电位；(3)确定染色质重塑蛋白Polycomb在神经前体细胞不对称分裂中的作用。这些研究将有助于理解控制多细胞生物中前体细胞自我更新和终端不对称分裂的途径。

DESCRIPTION (provided by applicant): In higher eukaryotes, certain tissues consist of a special type of cells known as stem cells. Stem cells divide to self-renew and at the same time to generate a progeny that is committed to a differentiation pathway. Although of much importance, very little is known of how a stem cell acquires its identity or how it functions. In Drosophila, the primary neuronal precursor cells (Neuroblasts, NB) function as stem cells and divide by self-renewing asymmetric mitosis. During neurogenesis, a NB self-renews and also produces a chain of ganglion mother cells (GMCs). A GMC is bipotential, it does not self-renew but divides asymmetrically to generate two distinct post-mitotic neurons. Thus, from -30 NBs in a given hemisegment, -320 distinct neurons are generated. This indicates that the ability of NBs to function as stem cells and the ability of NBs and GMCs to divide by asymmetric mitosis is crucial in generating a large number of neurons from a few precursor cells. Our long-term goal aims to explore the genetic regulation of self-renewing stem cell type of asymmetric divisions using the Drosophila CNS as our model system. In order to study the problem of self-renewing and terminal asymmetric divisions, we have selected several different CNS lineages: MP2, NB7-3, GMC-1->RP2/sib, and GMC-1->aCC/pCC lineages. During the past several years, we have identified through genetic screens mutations that show self-renewing and terminal asymmetric division in one or more of these lineages. In this grant we propose to further study these mutations. Thus, our specific aims include: (1) To investigate the role of Midline in inhibiting the self- renewing asymmetric division potential of neural precursor cells, and, 2) To determine how Neuralized-like inhibits the self-renewing asymmetric division potential of precursor cells, and 3) To determine the role of Polycomb, a chromatin re-modeling protein, in the asymmetric division of GMCs. These studies will help understand pathways that govern the self-renewing and terminal asymmetric division of precursor cells in multi-cellular organisms.