Genetic Control of Motor Neuron Development and Function

运动神经元发育和功能的遗传控制

• 批准号: 7423921
• 负责人: SAMUEL L. PFAFF
• 金额: $ 48.35万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-17 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7423921
• 关键词: Adult; Affect; Alleles; Amyotrophic Lateral Sclerosis; Animals; Axon; Behavioral Assay; Biochemical; Biochemistry; Biological Assay; Boxing; Category Rating Scale; Cells; Cephalic; Chick Embryo; Chromatin; Chromosome Pairing; Class; Code; Complement; Complex; Condition; Dependence; Development; Dextrans; Disease Pathway; Embryo; Environment; Ethylnitrosourea; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Crosses; Genetic Screening; Genetic Transcription; Goals; Grant; Histology; Histone Acetylation; Histones; Homologous Gene; Human; Image; Immunohistochemistry; In Situ Hybridization; Individual; Interneurons; Knock-out; Knockout Mice; Label; Light; Locomotion; Mediating; Methods; Methylation; Mind; Mitotic; Modification; Molecular; Monitor; Morphology; Motor; Motor Neuron Disease; Motor Neurons; Movement; Mus; Muscle Development; Mutagenesis; Mutation; Names; Neural Tube Development; Neural tube; Neurons; Neurotransmitters; Numbers; Pathway interactions; Phase; Phenotype; Principal Investigator; Process; Proteins; RNA; Range; Reporter; Research Personnel; Respiration; Role; Series; Signal Transduction; Specific qualifier value; Staging; Synapses; Techniques; Tertiary Protein Structure; Testing; TimeLine; Tissues; To specify; Transcriptional Regulation; Transgenic Organisms; acquired factor; axon guidance; base; cell motility; cell type; cofactor; combinatorial; design; dextran; embryonic stem cell; fly; gain of function; genetic analysis; in vivo; mature animal; member; mutant; neurotrophic factor; novel; pol genes; programs; promoter; protein protein interaction; receptor; research study; selective expression; stem; synaptogenesis; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): This grant is directed at understanding the molecular mechanisms that control the development and connectivity of motor neurons. Since these cells are needed to control movement and respiration, diseases of motor neurons (e.g. ALS and SMA) are extremely costly and frequently lethal due to the lack of any treatment. The two main goals of this application are to characterize the function and biochemistry of motor neuron transcription factors and to identify the genetic pathways involved in their proper development. Our past studies have shown that LIM-HD factors function in a combinatorial manner to specify individual motor neuron subtypes (LIM code). In this grant we will examine how LIM-HD factors acquire cell type specific activities through functional and genetic interactions with other transcription factors. We will test whether LIM-HD factors have temporally regulated functions that direct the sequential refinement of motor neuron identity and function. Finally, we will use "forward" mouse genetic screens to identify and characterize new genes involved in motor neuron development. The experiments in this grant rely extensively on mouse genetics using transgenic and knockout methods, biochemistry and transcription assays, explant assays and imaging, and ENU-based mutagenesis screens. In aim one we will examine the function of LIM-HD factors Isl1 and Isl2, LMO factor LMO4, and Tbx factor Tbx20 using mouse knockout mutations to define functional interactions between LIM-HD factors and other classes of transcription factors expressed by motor neurons. In aim two we will use biochemical assays to investigate how gene regulation is controlled during motor neuron differentiation. In aim three we will examine whether motor neuron transcription factors Isl1, LMO4, Hb9, and Tbx20 are required for the survival and proper function of post natal motor neurons, since this could shed new light on motor neuron disease pathways. In aim four we will characterize new genetic pathways involved in motor neuron development by characterizing genes identified through an END mutagenesis screen. Our studies should provide novel information about the molecular pathways that operate to control motor neuron specification, axon navigation, circuit formation, and survival in adults.

描述（由申请人提供）：这项资助旨在了解控制运动神经元发育和连接的分子机制。由于需要这些细胞来控制运动和呼吸，因此运动神经元疾病（例如 ALS 和 SMA）的成本极其高昂，并且由于缺乏任何治疗而常常致命。该应用的两个主要目标是表征运动神经元转录因子的功能和生物化学，并确定参与其正常发育的遗传途径。我们过去的研究表明，LIM-HD 因子以组合方式发挥作用，指定单个运动神经元亚型（LIM 代码）。在这笔资助中，我们将研究 LIM-HD 因子如何通过与其他转录因子的功能和遗传相互作用来获得细胞类型特异性活性。我们将测试 LIM-HD 因子是否具有指导运动神经元身份和功能的顺序细化的时间调节功能。最后，我们将使用“正向”小鼠遗传筛选来识别和表征参与运动神经元发育的新基因。这项资助中的实验广泛依赖于使用转基因和敲除方法、生物化学和转录测定、外植体测定和成像以及基于 ENU 的诱变筛选的小鼠遗传学。在目标一中，我们将使用小鼠敲除突变来检查 LIM-HD 因子 Isl1 和 Isl2、LMO 因子 LMO4 和 Tbx 因子 Tbx20 的功能，以定义 LIM-HD 因子与运动神经元表达的其他类别转录因子之间的功能相互作用。在目标二中，我们将使用生化测定来研究运动神经元分化过程中如何控制基因调控。在目标三中，我们将检查运动神经元转录因子 Isl1、LMO4、Hb9 和 Tbx20 是否是出生后运动神经元的存活和正常功能所必需的，因为这可能为运动神经元疾病途径提供新的线索。在目标四中，我们将通过表征通过 END 诱变筛选鉴定的基因来表征参与运动神经元发育的新遗传途径。我们的研究应该提供有关控制运动神经元规范、轴突导航、回路形成和成人生存的分子途径的新信息。