Molecular Genetics of Stem Cell in Drosophila

描述(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。干细胞分裂以自我更新，同时产生致力于分化途径的后代。尽管很重要，但人们对干细胞如何获得其身份或如何发挥作用知之甚少。在果蝇中，初级神经前体细胞(神经母细胞，NB)作为干细胞发挥作用，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，神经节细胞会自我更新并产生一系列神经节母细胞(GMC)。GMC是双潜能的，它不会自我更新，而是不对称地分裂，产生两个不同的有丝分裂后神经元。因此，在给定的半节段中，来自-30个NBS的-320个不同的神经元被产生。这表明NBS作为干细胞的功能以及NBS和GMCs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产生大量神经元是至关重要的。我们的长期目标是以果蝇中枢神经系统为模型系统，探索自我更新干细胞型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-&GT；RP2/sib，以及GMC-1-&GT；ACC/PCC谱系。在过去的几年里，我们已经通过基因筛查确定了在这些谱系中的一个或多个中显示自我更新和末端不对称分裂的突变。在这项拨款中，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潜能中的作用，以及(2)确定神经元样如何抑制前体细胞的自我更新的不对称分裂潜力，以及(3)确定染色质重塑蛋白Polycomb在GMC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体中前体细胞的自我更新和末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.