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: 7373577
• 负责人: Kathleen Joyce Millen
• 金额: $ 33.44万
• 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/7373577
• 关键词: Anterior; Biological; Brain; Cell Proliferation; Cerebellar malformation; Cerebellum; Cerebral cortex; Congenital Abnormality; Dandy-Walker Syndrome; Defect; Development; Dorsal; Embryo; Gene Targeting; Genes; Holoprosencephaly; Human; Interneurons; Left; Mesenchymal; Mus; Mutant Strains Mice; Mutation; Neurologic Mutants Mice; Neurons; Pattern; Pattern Formation; Phenotype; Residual state; Role; Roof of the Fourth Ventricle; Sensory; Signal Transduction; Spinal Cord; Structure; Technology; Telencephalon; Testing; Transgenic Organisms; base; brain malformation; genetic analysis; genetic technology; hindbrain; homeodomain; malformation; mutant; neuronal growth; research study

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）：

项目成果

Zac1 plays a key role in the development of specific neuronal subsets in the mouse cerebellum.

• DOI: 10.1186/1749-8104-6-25
• 发表时间: 2011-05-18
• 期刊: Neural development
• 影响因子: 3.6
• 作者: Chung SH;Marzban H;Aldinger K;Dixit R;Millen K;Schuurmans C;Hawkes R
• 通讯作者: Hawkes R