Mechanism of a novel cause of spina bifida

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学，以及具体的挑战主题，15- ns -106：识别神经系统发育和功能基础的机制。本挑战赛征集阐明神经系统形成原理的机制研究，以及对神经系统疾病中正常机制如何受到干扰的分析。脊柱裂是人类最常见的结构畸形之一；尽管其高死亡率和发病率，脊柱裂的病因仍然知之甚少。我们提出对Noggin突变小鼠腰椎脊柱裂原因的机制分析。与几乎所有其他具有神经管缺陷的小鼠品系相比，Noggin的脊柱裂表型不是由于背神经褶皱无法闭合到神经管中而发生的。相反，闭合后一天左右，腰椎脊髓沿中线在孤立区域重新向背打开。这导致腰椎裂的表型。这种突变体代表了一种新的小鼠模型，用于研究脊柱裂的未知机制，与神经管无法关闭的模型相比，这种模型可能与一些人类脊柱裂病例的发病机制更相关。我们使用组织特异性基因消融来确定个体组织对Noggin维持神经功能的需求。我们的初步数据表明，Noggin促进神经管细胞对细胞粘附分子（如n -钙粘蛋白）的粘附。我们的总体假设是在沿背神经管闭合的缝中需要Noggin来维持闭合。我们测试这以及替代模型，并评估下游分子和细胞途径。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science, and the specific Challenge Topic, 15-NS-106: Identifying mechanisms that underlie nervous system development and function. This Challenge solicits mechanistic studies that elucidate principles of nervous system formation, as well as analyses of how normal mechanisms are perturbed in neurological disease. Spina bifida is one of the most common structural malformations in man; despite its high mortality and morbidity, the etiological causes of spina bifida remain poorly understood. We propose a mechanistic analysis of the causes of lumbar spina bifida in Noggin mutant mice. In contrast to virtually all other mouse strains with neural tube defects, the spina bifida phenotype in Noggin does not occur through a failure of the dorsal neural folds to close into a tube. Rather, a day or so after closure the lumbar spinal cord reopens dorsally in isolated regions along the midline. This results in a lumbar spina bifida phenotype. This mutant represents a novel mouse model for an unexplored mechanism of spina bifida that is likely to be more relevant to pathogenesis of some human cases of spina bifida than models in which the neural tube fails to close. We use tissue-specific gene ablation to determine the individual tissue requirements Noggin for maintenance of neurulation. Our preliminary data indicate that Noggin promotes adhesion of neural tube cells to cell adhesion molecules such as N-cadherin. Our overall hypothesis is that Noggin is required in the closed seam along the dorsal neural tube for maintenance of closure. We test this as well as alternative models, and evaluate downstream molecular and cellular pathways. PUBLIC HEALTH RELEVANCE: This Challenge Grant application addresses mechanisms of spina bifida using the mouse model system. Using a genetic approach, complemented with molecular and cellular assays, we dissect the developmental cause(s) of the fully penetrant spina bifida phenotype in mouse noggin mutants. Spina bifida is poorly understood in humans, yet affects affects approximately 2,000 of the approximately 4 million babies born each year in the US. Although usually not fatal in live-born infants if repaired surgically, lifetime complications typically occur, at an average cost of over $1 million per case.