Investigating the Molecular Bases of Class-Specific Dendrite Morphogenesis

描述(申请人提供)：阐明类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神经回路以及与神经和神经退行性疾病有关，在这些疾病中，树突异常可能表现为认知功能受损。果蝇已经成为剖析这些机制的一个强有力的模型。虽然有重要的证据表明，复杂的转录调控程序能够产生细胞类型的特定树突形态，但仍不清楚的是这些程序的下游实施，以及哪些细胞、分子和生物过程能够使树突形态发生这些变化。目前的建议将通过关注关键的下游效应因子来解决这一知识差距，进化上保守的同源结构域转录因子通过这些效应因子介导类特异性树突的树枝形成和动态平衡。我们将检验三个中心假说：1)CUT通过调节基础自噬途径来差异地调节一类特定感觉神经元树突的树突分枝和内稳态；2)由CG3995编码的新的锌指床型蛋白作为CUT的下游因子，并在功能上与核糖体蛋白相互作用，指导细胞型特异性树突的形态发生；以及3)进化上保守的HOX蛋白，触角蛋白和性Combs减少，其功能与CUT一起差异地介导细胞型特异性树突形态。拟议研究的短期影响将是对转录控制对果蝇不同树突形态发生影响的细胞和分子机制的新见解。最终，这些研究有可能确定进化上保守的调控机制，这些机制管理人类的树突发育/内稳态，并可能有助于我们理解这些细胞过程中的错乱可能如何导致神经和神经退行性疾病状态。 与公共健康相关：树突主要专门用于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神经系统至关重要。此职能角色如中所示 一系列不同的神经病理和神经退行性疾病状态，包括阿尔茨海默氏症、智力低下和自闭症，在树突缺陷和认知障碍之间存在着强烈的神经解剖学相关性。这些研究旨在阐明关键的分子和细胞程序，这些程序在指导和维持细胞型特定树突状细胞的形态发生和动态平衡方面发挥作用。

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.