Regulation of dendrite morphogenseis by Nanos and Pumilio

描述（由申请人提供）：树突乔木的组织决定了神经元对细胞外信号做出反应的有效性。尽管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，但对于随后如何细化和维持分支模式却知之甚少。果蝇幼虫中已充分表征的树突状树枝化 (da) 神经元对于识别对树突形态发生重要的基因至关重要。 Nanos (Nos) 和 Pumilio (Pum) 最初被鉴定为果蝇胚胎中翻译抑制复合物的一部分，它们是维持高度分支的 IV 类 da 神经元中树突状树枝化所必需的。我们的目标是确定对树突形态发生至关重要的 Nos 和 Pum 功能的下游靶标。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) 表达的增加所致。通过凋亡途径成员介导的 caspase 活性的非凋亡功能对于许多发育过程都很重要，包括变态过程中 IV 类 da 神经元的修剪和树突重塑。我们提出生化和遗传分析来检验这样的假设：Nos/Pum 复合物通过调节 hid 来调节非凋亡 caspase 功能，以便在变态之前维持幼虫 IV 类 da 神经元的树突复杂性。此外，基因抑制筛选将使我们能够识别树突形态发生所需的 Nos/Pum 的其他下游靶标。 公共卫生相关性：神经元形态发生缺陷可导致多种神经系统疾病；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神经系统功能和完整性所必需的途径。该培训提案将重点关注对树突分枝很重要的转录后调节机制的特征，并使我们更好地了解某些途径和/或因素的调节如何影响正常神经元发育。

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.