Investigating the Molecular Bases of Class-Specific Dendrite Morphogenesis

研究类特异性树突形态发生的分子基础

基本信息

批准号：
8433892
负责人：
Daniel N Cox
金额：
$ 43.07万
依托单位：
GEORGE MASON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433892
关键词：
Address Afferent Neurons Alzheimer&apos s Disease Autistic Disorder Autophagocytosis Biological Process Cell physiology Comb animal structure Complex Defect Dendrites Development Drosophila genus Drosophila melanogaster Gene Expression Genes Genetic Homeodomain Proteins Homeostasis Human Impaired cognition Knowledge Maintenance Mediating Mental Retardation Modeling Molecular Morphogenesis Morphology Nervous system structure Neurodegenerative Disorders Neurons Pathway interactions Pharmaceutical Preparations Process Protein Biochemistry Proteins Proteomics Recruitment Activity Regulation Ribosomal Proteins Role Structure Testing Transcriptional Regulation Zinc Fingers base cell type cellular imaging cognitive function homeodomain in vivo insight nervous system disorder neural circuit novel programs protein aggregate sex transcription factor

项目摘要

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.

描述（由申请人提供）：阐明类特异性树突发生的细胞和分子机制在形态学上非常重要，因为适当的树突发育对于功能性神经回路的建立和维持以及与神经系统和神经退行性疾病的关系至关重要。树突异常可能表现为认知功能受损。果蝇已成为剖析这些机制的强大模型。虽然重要的证据表明复杂的转录调控程序能够产生细胞类型特异性的树突形态，但人们对这些程序的下游实施以及招募哪些细胞、分子和生物过程来实现树突形态的这些变化仍然知之甚少。目前的提案将通过关注关键的下游效应器来解决这一知识差距，进化上保守的 Cut 同源域转录因子通过这些效应器介导类特异性树突分枝和稳态。我们将测试三个中心假设：1）Cut 通过调节基础自噬途径差异性地调节类别特异性感觉神经元树突树枝化和稳态； 2) 由CG3995编码的新型锌指BED型蛋白作为Cut的下游效应子发挥作用，并与核糖体蛋白功能性相互作用以指导细胞类型特异性树突形态发生； 3) 进化上保守的 Hox 蛋白、触角足和性梳减少，与 Cut 一起发挥作用，以差异介导细胞类型特异性树突形态。拟议研究的短期影响将是对转录控制对果蝇差异树突形态发生产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控制人类树突发育/稳态的进化保守的调节机制，并可能有助于我们理解这些细胞过程中的紊乱如何可能成为神经和神经退行性疾病状态的基础。公共健康相关性：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性神经系统至关重要。这种功能作用如图所示一系列不同的神经病理学和神经退行性疾病状态，包括阿尔茨海默病、智力低下和自闭症，其中树突缺陷和认知障碍之间存在很强的神经解剖学相关性。拟议的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方面发挥作用的关键分子和细胞程序。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cut, via CrebA, transcriptionally regulates the COPII secretory pathway to direct dendrite development in Drosophila.

Cut 通过 CrebA 在转录上调节 COPII 分泌途径，以指导果蝇树突的发育。

DOI：
发表时间：
2013-10-15
期刊：
影响因子：
4
作者：
Iyer, Srividya Chandramouli;Ramachandran Iyer, Eswar P;Meduri, Ramakrishna;Rubaharan, Myurajan;Kuntimaddi, Aravinda;Karamsetty, Madhu;Cox, Daniel N
通讯作者：
Cox, Daniel N

Sensing the cold: TRP channels in thermal nociception.

感知寒冷：热伤害感受中的 TRP 通道。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Himmel, Nathaniel J;Cox, Daniel N
通讯作者：
Cox, Daniel N

Turtle functions downstream of Cut in differentially regulating class specific dendrite morphogenesis in Drosophila.

Turtle 在果蝇中 Cut 下游发挥差异调节类特异性树突形态发生的作用。

DOI：
发表时间：
2011
期刊：
影响因子：
3.7
作者：
Sulkowski, Mikolaj J;Iyer, Srividya Chandramouli;Kurosawa, Mathieu S;Iyer, Eswar Prasad R;Cox, Daniel N
通讯作者：
Cox, Daniel N

Growing pains: development of the larval nocifensive response in Drosophila.

生长痛：果蝇幼虫伤害反应的发展。