Genetic Analysis of Roof Plate Function in the CNS

中枢神经系统顶板功能的遗传分析

• 批准号: 6908875
• 负责人: Kathleen Joyce Millen
• 金额: $ 34.8万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908875
• 关键词: cell proliferation; central nervous system; cerebellar cortex; developmental genetics; developmental neurobiology; gene targeting; genetic regulation; genetically modified animals; green fluorescent proteins; immunocytochemistry; in situ hybridization; laboratory mouse; neural plate /tube; phenotype; telencephalon

DESCRIPTION (provided by applicant): We are studying dorsal CNS pattern formation in the mouse, as a paradigm for human congenital brain malformations based on the hypothesis that similar patterning defects underlie mouse and human malformations. Pattern formation is the term used to describe the emergence of spatial biological organization during development. Malformations of the dorsal midline of the human CNS are poorly understood congenital defects that include some forms of holoprosencephaly and megalencephaly. Both of these are primarily malformations of the dorsal cortex. An example of a dorsal midline malformation of the cerebellum is Dandy-Walker Malformation. The roof plate is a specialized dorsal midline structure in the embryonic CNS. It is a crucial regulator of dorsal patterning information in the developing spinal cord, directing the specification and differentiation of dorsal sensory interneurons via secreted molecules. We hypothesize that the roof plate performs a similar function in more anterior levels in the brain. Specifically, we hypothesize that the Lim-homeodomain encoding genes, Lmx 1a and Lmx 1b are required for normal roof plate development in the anterior CNS and that loss of these genes leads to loss of roof plate function and subsequent abnormal specification and differentiation of adjacent neurons in the developing cerebellum and cortex. We have previously demonstrated that the spontaneous neurological mouse mutant, dreher, harbors mutations in the Lmx 1a gene and that Lmx 1a is required for roof plate development in the mouse CNS. In the dreher spinal cord, no roof plate is generated. Consequently, the specification, patterning and differentiation of adjacent dorsal sensory interneurons are abnormal in the dreher spinal cord. At anterior levels of the developing CNS, a residual roof plate is still present in dreher mice, suggesting that roof plate in the brain has a different mechanism of genesis. This proposal makes use of gene targeting and transgenic technology in combination with extensive phenotypic analysis to examine the roles of Lmx 1a and the closely related gene, Lmx 1b, in roof plate formation and function adjacent to the developing cerebellum and cerebral cortex.

描述（由申请人提供）： 我们正在研究背侧中枢神经系统模式形成的小鼠，作为人类先天性脑畸形的基础上，类似的图案缺陷的假设，小鼠和人类畸形的范例。模式形成是用来描述空间生物组织在发育过程中出现的术语。人类中枢神经系统背中线的畸形是一种知之甚少的先天性缺陷，包括前脑无裂畸形和巨脑畸形。这两种都是背侧皮质的畸形。小脑背中线畸形的一个例子是Dandy-Walker畸形。顶板是胚胎中枢神经系统背中线的特化结构。它是发育中脊髓背侧图案信息的关键调节剂，通过分泌的分子指导背侧感觉中间神经元的特化和分化。我们假设顶板在大脑更前部的水平上执行类似的功能。具体而言，我们假设，Lim-homeodomain编码基因，Lmx 1a和Lmx 1b是必需的前中枢神经系统的正常顶板的发展，这些基因的损失导致顶板功能的丧失和随后的异常规范和分化的相邻神经元在发展中的小脑和皮质。我们以前已经证明，自发的神经系统小鼠突变，dreher，窝藏突变的Lmx 1a基因和Lmx 1a是必需的顶板发展在小鼠中枢神经系统。在dreher脊髓中，没有顶板生成。因此，在dreher脊髓中，相邻的背侧感觉中间神经元的特化、图案化和分化是异常的。在发育中的中枢神经系统的前部水平，残余的顶板仍然存在于dreher小鼠中，这表明大脑中的顶板具有不同的发生机制。该建议利用基因打靶和转基因技术结合广泛的表型分析来研究Lmx 1a和密切相关的基因Lmx 1b在发育中的小脑和大脑皮层附近的顶板形成和功能中的作用。