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）：沿脊椎动物脊髓背腹轴的细胞类型的初始规范需要 Sonic Hedgehog (Shh)、Nodal 和 BMP 信号通路的活动。已知这些信号通路中许多成分的突变会导致人类出生缺陷和肿瘤。因此，了解这些信号通路在体内如何发挥作用对于人类健康具有明显的重要意义。该实验室已经发现了 7 种 ENTJ 诱导的小鼠突变，这些突变改变了脊髓背腹轴上的细胞命运。所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突变，是Shh 通路的重要组成部分。其中一个突变是开放脑 (opb) 基因的等位基因，实验室显示该基因编码 Rab23，并充当 Shh 通路的负调节因子。其他五个基因似乎是新颖的，因为它们映射到的区域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 途径中的哪一步受 Opb/Rab23 控制。 Rab23 的亚细胞定位将被表征，并且其在控制已知在 Shh 信号通路中起作用的蛋白质的定位中的作用将被确定。将研究 Rab23 的果蝇同源物。如果果蝇基因在 Hedgehog 途径中发挥作用，则果蝇中可用的试剂和技术将用于确定该基因的作用机制。一种新的小鼠基因 wimple (wim) 将被表征。 wim 突变体缺乏脊髓腹侧细胞类型，缺乏正常的左右不对称性，初步数据表明 wim 可能在 Shh 通路中的 Patched 下游发挥作用。基于图谱的策略将用于鉴定 wim 基因，并对 Wim 蛋白的功能进行表征。筛选中发现的另外四种影响脊髓早期背腹模式的新突变将在遗传上进行表征。这些实验将确定控制神经模式的信号通路的新组成部分，并将定义早期背腹神经细胞类型规范所必需的过程。