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Linking motorneuron fate and connectivity in Drosophila

连接果蝇运动神经元的命运和连接

基本信息

批准号：
7779973
负责人：
Heather Broihier
金额：
$ 30.08万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7779973
关键词：
Affect Alleles Axon Behavior Biological Biological Assay Biological Models Cells Characteristics Cleaved cell Clinical Cues Data Defect Development Disease Drosophila genus Embryo Event Exhibits Extracellular Matrix Family Genes Genetic Genetic Epistasis Genetic Models Goals Growth Cones Human Development In Vitro Insulin Signaling Pathway Invertebrates Link Matrix Metalloproteinases Medical Metalloproteases Mitotic Modeling Molecular Molecular Genetics Motor Motor Neurons Nervous system structure Neuronal Differentiation Neurons Pathway interactions Pattern Peptide Hydrolases Phenotype Play Population Postdoctoral Fellow Proteins Research Research Personnel Role Screening procedure Series Signal Pathway Signal Transduction Stereotyping Synapses System Transcriptional Regulation Translating axon guidance base extracellular gain of function genetic analysis in vivo interest mutant neural circuit neuromuscular neuron development novel overexpression programs research study response synaptogenesis transcription factor

项目摘要

Our long term aim is to use a genetic approach in Drosophila to understand molecular mechanisms of motorneuron fate specification and differentiation. In this proposal, we focus on mechanisms linking motorneuron fate to axon guidance. In a large-scale screen for mutants affecting motorneuron development, we have identified foxO and Mmp2, both of which are expressed in motorneuron subsets and necessary for proper motor axon guidance. We focus on these two evolutionarily-conserved proteins as they provide us with novel entry points for elucidating how distinct behaviors of motorneurons are developmentally regulated. Our goals here are to complete molecular, genetic, and phenotypic analyses of these genes in order to understand the observed mutant phenotypes. FoxO is a transcription factor best known for its role in the insulin signaling pathway where it is regulated by extracellular signals. Our preliminary data suggest that FoxO is expressed specifically in clusters of motorneurons in response to a target-derived signal. Detailed expression and phenotypic analyses will elucidate the role of FoxO in motorneuron development. Furthermore, we will identify the signaling pathway(s) regulating FoxO expression in motorneurons through molecular and genetic epistasis experiments. Matrix metalloproteinases (Mmps) comprise a large family of. transmembrane and secreted proteases that together cleave nearly every component of the ECM.Mmp2 is expressed in stereotyped populations of motorneurons and is necessary for proper motor axon guidance. We will characterize the expression pattern of Mmp2 in post-mitotic neurons and elucidate its role in motor axon guidance by analyzing motor axon outgrowth in Mmp2 mutant embryos. Additionally, we will establish whether Mmp2 is necessary for motor axon defasciculation by analyzing genetic interactions between Mmp2 and guidance molecules known to regulate this key pathfinding step. These studies will advance our understanding of how molecules acting in distinct motorneuron populations coordinate to establish proper patterns of neuromuscular connectivity. Motorneuron differentiation is an essential event in neuronal development and can be disrupted in human development and disease. Furthermore, since both foxO and Mmp2 are evolutionarily-conserved proteins acting in pathways of intense clinical interest, these studies should have broad biological and medical significance.

我们的长期目标是在果蝇中使用遗传学方法来理解运动神经元命运的特化和分化。在这一建议中，我们侧重于将运动神经元的命运轴突指导。在一项影响运动神经元发育的突变体的大规模筛选中，我们已经鉴定了foxO和Mmp2，它们都在运动神经元亚群中表达，并且是运动神经元的必需的。正确的运动轴突引导我们关注这两种进化上保守的蛋白质，因为它们为我们提供了具有新的切入点，用于阐明运动神经元的不同行为是如何发育调节的。我们的目标是完成这些基因的分子、遗传和表型分析，了解观察到的突变体表型。FoxO是一种转录因子，最为人所知的是其在转录调控中的作用。胰岛素信号传导途径，其中其由细胞外信号调节。我们的初步数据显示， FoxO在运动神经元簇中特异性表达，以响应靶源信号。详细表达和表型分析将阐明FoxO在运动神经元发育中的作用。此外，我们将通过以下途径鉴定调节运动神经元中FoxO表达的信号通路：分子和遗传上位性实验。基质金属蛋白酶（Mmps）是一个大家族。跨膜和分泌的蛋白酶一起切割几乎ECM的每一个组分。表达于刻板的运动神经元群体中，并且是正确的运动轴突引导所必需的。我们将描述Mmp2在有丝分裂后神经元中的表达模式，并阐明其在运动神经元中的作用。通过分析Mmp2突变胚胎中的运动轴突生长来指导轴突生长。此外，我们将建立通过分析Mmp2与运动神经元之间的遗传相互作用，以及已知的调节这一关键寻路步骤的引导分子。这些研究将推动我们的了解分子如何在不同的运动神经元群体协调，以建立适当的神经肌肉连接的模式运动神经元的分化是神经元分化的重要事件。发展，并可能在人类发展和疾病中被破坏。此外，由于foxO和 mmp 2是进化上保守的蛋白质，在临床上具有重要意义，这些研究应该具有广泛的生物学和医学意义。