Genetic Analysis of Mouse Nervous System Development

小鼠神经系统发育的遗传分析

• 批准号: 6748520
• 负责人: Kathryn V Anderson
• 金额: $ 37.64万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748520
• 关键词: cell type; developmental genetics; developmental neurobiology; genetic strain; laboratory mouse; laboratory rabbit; mammalian embryology; neurogenesis; protein localization; spinal cord

DESCRIPTION (provided by applicant): The initial specification of cell types along dorsal-ventral axis of the vertebrate spinal cord requires the activities of the Sonic hedgehog (Shh), Nodal and BMP signaling pathways. Mutations in many of the components in these signaling pathways are known to cause human birth defects and tumors. Thus understanding how these signaling pathways function in vivo is of clear importance for human health. The lab has identified seven ENTJ-induced mouse mutations that change cell fate along the dorsalventral axis of the spinal cord. The experiments proposed will define how these mutations affect neural patterning. One mutation is allelic to smoothened, an essential component of the Shh pathway. One mutation is an allele of the open brain (opb) gene, which the lab showed encodes Rab23 and acts as a negative regulator of the Shh pathway. The other five genes appear to be novel, because they map to regions that do not include genes previously implicated in neural patterning. Genetic analysis will be used to determine which step in the Shh pathway is controlled Opb/Rab23. The subcellular localization of Rab23 will be characterized and its role in controlling the localization of proteins known to act in the Shh signaling pathway will be determined. The Drosophila homologue of Rab23 will be studied. If the Drosophila gene acts in the Hedgehog pathway, reagents and techniques available in Drosophila will be used to define the mechanism of action of this gene. A novel mouse gene, wimple (wim), will be characterized. wim mutants lack ventral cell types in the spinal cord lack normal left-right asymmetry, and preliminary data suggest that wim may act downstream of Patched in the Shh pathway. Map-based strategies will be used to identify the wim gene, and the function of the Wim protein will be characterized. Four additional novel mutations identified in the screen that affect early dorsal-ventral patterning the spinal cord will be characterized genetically. These experiments will identify new components of the signaling pathways that control neural patterning and will define the processes that are essential for early dorsal-ventral neural cell type specification.

描述（由申请人提供）：脊椎背侧腹侧轴沿脊髓背腹轴的初始规范需要Sonic刺猬（SHH），Nodal和BMP信号传导途径的活动。这些信号通路中许多组件中的突变已知会导致人类的先天缺陷和肿瘤。因此，了解这些信号通路在体内的功能对于人类健康至关重要。该实验室已经鉴定出七个ENTJ诱导的小鼠突变，这些突变改变了沿脊髓的背侧轴的细胞命运。提出的实验将定义这些突变如何影响神经模式。一个突变是等位基因到平滑的，这是SHH途径的重要组成部分。一个突变是开放脑（OPB）基因的等位基因，实验室表现出编码Rab23并充当SHH途径的负调节剂。其他五个基因似乎是新颖的，因为它们映射到不包括先前与神经模式有关的基因。遗传分析将用于确定SHH途径中的哪个步骤受控制的OPB/RAB23。将确定RAB23的亚细胞定位，并在控制已知在SHH信号通路中作用的蛋白质定位中的作用。将研究Rab23的果蝇同源物。如果果蝇基因在刺猬途径中起作用，则果蝇中可用的试剂和技术将用于定义该基因的作用机理。新颖的小鼠基因Wimple（WIM）将被表征。 WIM突变体缺乏脊髓中的腹侧细胞类型缺乏正常的左右不对称性，而初步数据表明WIM可能在SHH途径中的斑块下游作用。基于地图的策略将用于识别WIM基因，并且将表征WIM蛋白的功能。在屏幕上鉴定出的另外四个新型突变会影响脊髓早期的背腹形成图案。这些实验将确定控制神经模式的信号传导途径的新组成部分，并定义对早期背腹神经细胞类型规范必不可少的过程。