Regulation of dendrite morphogenseis by Nanos and Pumilio

描述（由申请人提供）：树突状乔木的组织决定了神经元对细胞外信号的反应效率。虽然已经确定了许多因素是必不可少的，在发展过程中建立树突状形态，少得多的是知道如何分支模式随后细化和维护。在果蝇幼虫中的树突状分支（da）神经元的特点是在识别树突形态发生的重要基因的基础。Nanos（Nos）和Pumilio（Pum）首先被鉴定为果蝇胚胎中翻译抑制复合物的一部分，需要在高度分支的IV类DA神经元中维持树突状分支。我们的目标是确定下游目标的Nos和Pum功能是必不可少的树突形态发生。我们实验室最近的遗传分析表明，在NOS和泵缺陷的幼虫中观察到的树突状树枝化的缺陷部分来自促凋亡因子头退化缺陷（Hid）的表达增加。caspase活性的非凋亡功能，介导的凋亡途径的成员，是重要的许多发育过程中，包括修剪和树突重塑的IV类DA神经元在变态。我们提出了生化和遗传分析来测试的假设，即NOS/Pum复杂的调制非凋亡caspase功能，通过调节HID，以保持树突状复杂性幼虫IV类DA神经元变态前。此外，遗传抑制屏幕将使我们能够确定其他下游目标的Nos/Pum所需的树突形态发生。 公共卫生相关性：神经元形态发生的缺陷可能导致许多神经系统疾病;因此，描述导致神经元正常发育的基因调节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。这项培训计划将侧重于表征转录后调控机制，这些机制对树突状树枝化很重要，并将使我们更好地了解某些途径和/或因子的调控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.