Investigating the Molecular Bases of Class-Specific Dendrite Morphogenesis

描述（由申请人提供）：阐明类别特异性树突发生的细胞和分子机制在形态学上很重要，因为正确的树突发育对于建立和维持功能性神经回路至关重要，并且与神经和神经退行性疾病有关，其中树突异常可能表现为认知功能受损。黑腹果蝇已经成为剖析这些机制的有力模型。虽然有大量证据表明，复杂的转录调控程序的功能，以产生细胞类型特异性树突形态，仍然知之甚少的是这些程序的下游实施和细胞，分子和生物过程招募，使这些树突形态的变化。目前的建议将解决这一知识差距，重点放在关键的下游效应，进化保守的切割同源结构域转录因子介导类特异性树突树枝化和稳态。我们将测试三个中心假设：1）Cut通过调节基础自噬途径来差异调节类别特异性感觉神经元树突分支和稳态; 2）由CG 3995编码的新型锌指BED型蛋白作为Cut的下游效应子起作用，并且在功能上与核糖体蛋白相互作用以指导细胞类型特异性树突形态发生;和3）进化上保守的Hox蛋白质，Apneapedia和Sex Combs Reduced，与Cut一起发挥功能，以差异介导细胞类型特异性树突形态。短期的影响，拟议中的研究将是新的见解的细胞和分子机制，转录控制在果蝇的差异树突形态发生的影响。最终，这些研究有可能确定进化上保守的调控机制，这些机制控制人类树突发育/稳态，并可能有助于我们理解这些细胞过程中的紊乱如何成为神经系统和神经退行性疾病状态的基础。 公共卫生相关性：树突主要专门接收和处理神经元输入，因此驱动树突形态的分子机制对于建立和维持功能性神经系统至关重要。这一职能作用见 多种神经病理学和神经变性疾病状态，包括阿尔茨海默氏症、精神发育迟滞和自闭症，其中树突缺陷和认知障碍之间存在强烈的神经解剖学相关性。这些研究旨在阐明在指导和维持细胞类型特异性树突形态发生和稳态中起作用的关键分子和细胞程序。

DESCRIPTION (provided by applicant): Elucidating the cellular and molecular mechanisms underlying class-specific dendritogenesis is important morphologically, as proper dendrite development is essential for the establishment and maintenance of functional neural circuitry, as well as in relation to neurological and neurodegenerative disease in which dendritic abnormalities may manifest as impaired cognitive function. Drosophila melanogaster has emerged as a powerful model for dissecting these mechanisms. While significant evidence demonstrates that complex transcriptional regulatory programs function to generate cell-type specific dendritic morphologies, what remains poorly understood is the downstream implementation of these programs and what cellular, molecular and biological processes are recruited to enable these changes in dendrite morphology. The current proposal will address this knowledge gap by focusing on key downstream effectors by which the evolutionarily conserved Cut homeodomain transcription factor mediates class-specific dendrite arborization and homeostasis. We will test three central hypotheses: 1) that Cut differentially regulates class specific sensory neuron dendrite arborization and homeostasis via regulation of the basal autophagy pathway; 2) that a novel zinc-finger BED- type protein encoded by CG3995 functions as a downstream efector of Cut and functionally interacts with ribosomal proteins to direct cell-type specific dendrite morphogenesis; and 3) that the evolutionarily conserved Hox proteins, Antennapedia and Sex Combs Reduced, function with Cut to differentially mediate cell-type specific dendritic morphologies. The short-term impact of the proposed studies will be novel insight into the cellular and molecular machinery by which transcriptional control exerts effects on differential dendrite morphogenesis in Drosophila. Ultimately, these studies have the potential to identify evolutionarily conserved regulatory mechanisms that govern dendrite development/homeostasis in humans and potentially contribute to our understanding of how derangements in these cellular processes may underlie neurological and neurodegenerative disease states. PUBLIC HEALTH RELEVANCE: Dendrite are primarily specialized to receive and process neuronal inputs and thus the molecular mechanisms that drive dendritic morphology are critical to establishing and maintaining a functional nervous system. This functional role is illustrated in a diverse array of neuropathological and neurodegenerative disease states including Alzheimer's, mental retardation, and Autism in which strong neuroanatomical correlates exist between dendrite defects and cognitive impairments. The proposed studies aim to elucidate key molecular and cellular programs that function in directing and maintaining cell-type specific dendrite morphogenesis and homeostasis.