Regulation of dendrite morphogenseis by Nanos and Pumilio

描述(由申请人提供)：树突的组织决定了神经元对细胞外信号的反应有多有效。虽然已经确定了在发育过程中建立树突形态所必需的许多因素，但关于分支模式随后是如何细化和保持的知之甚少。果蝇幼虫的树突状树枝(Da)神经元是鉴定树突形态发生的重要基因的基础。Nanos(Nos)和Pum(Pum)最初被鉴定为果蝇胚胎中翻译抑制复合体的一部分，它们需要维持高分支的IV类da神经元的树突树枝形成。我们的目标是确定对树突形态发生至关重要的NOS和Pum功能的下游靶点。我们实验室最近的遗传分析表明，在nos和pum缺陷的幼虫中观察到的树突分枝缺陷部分是由于促凋亡因子头部退化缺陷(HID)的表达增加所致。Caspase活性的非凋亡性功能通过凋亡途径的成员介导，在许多发育过程中都是重要的，包括在变态过程中IV类da神经元的修剪和树突重塑。我们提出了生化和遗传分析来验证这一假说，即Nos/Pum复合体通过调节HID来调节非凋亡性caspase功能，以便在幼虫IV类da神经元变态之前维持树突的复杂性。此外，基因抑制屏幕将使我们能够确定树突形态发生所需的其他NOs/Pum下游靶点。 与公共卫生相关：神经元形态发生缺陷可导致一系列神经系统疾病；因此，表征导致神经元正常发育的基因调控机制可以深入了解对神经系统功能和完整性至关重要的途径。这项培训计划将集中于表征转录后调控机制，这些机制对树突树枝形成非常重要，并将使我们更好地理解某些途径和/或因素的调控如何影响正常的神经元发育。

DESCRIPTION (provided by applicant): The organization of dendritic arbors dictates how effectively a neuron can respond to extracellular signals. Although many factors have been identified that are essential for establishing dendritic morphology during development, much less is known about how the branching patterns are subsequently refined and maintained. The well-characterized dendritic arborization (da) neurons in the Drosophila larva have been fundamental in identifying genes that are important for dendrite morphogenesis. Nanos (Nos) and Pumilio (Pum), which were first identified as part of a translational repression complex in the Drosophila embryo, are required to maintain dendritic arborization in the highly branched class IV da neurons. We aim to identify the downstream targets of Nos and Pum function that are essential for dendrite morphogenesis. Recent genetic analyses from our lab suggest that the defects in dendritic arborization observed in nos- and pum-deficient larvae arise partially from an increase in expression of the pro-apoptotic factor Head involution defective (Hid). Nonapoptotic functions of caspase activity, mediated through members of the apoptotic pathway, are important for many developmental processes, including pruning and dendrite remodeling of class IV da neurons during metamorphosis. We propose biochemical and genetic analyses to test the hypothesis that the Nos/Pum complex modulates nonapoptotic caspase function through regulation of hid in order to maintain dendritic complexity in larval class IV da neurons prior to metamorphosis. In addition, a genetic suppression screen will enable us to identify other downstream targets of Nos/Pum that are required for dendrite morphogenesis. PUBLIC HEALTH RELEVANCE: Defects in neuronal morphogenesis can lead to a number of neurological disorders; therefore, characterizing the mechanisms of gene regulation that lead to proper neuronal development can give insight into the pathways that are essential for nervous system function and integrity. This training proposal will focus on characterizing post-transcriptional regulatory mechanisms that are important for dendritic arborization and will give us a better understanding of how regulation of certain pathways and/or factors impinge on normal neuronal development.