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）转化科学和特定的挑战主题，15-NS-106：确定神经系统发育和功能的基础机制。这个挑战征求机制研究，阐明神经系统形成的原则，以及正常机制如何在神经系统疾病的干扰分析。脊柱裂是人类最常见的结构畸形之一，尽管其死亡率和发病率很高，但其病因仍知之甚少。我们提出了一个机制分析的原因，腰椎裂的Noggin突变小鼠。与几乎所有其他神经管缺陷的小鼠品系相反，Noggin的脊柱裂表型并不是通过背侧神经褶皱闭合成管失败而发生的。相反，在闭合后一天左右，腰椎脊髓在沿着中线的孤立区域背侧重新开放。这导致腰椎裂表型。这种突变体代表了一种新的小鼠模型，用于脊柱裂的未探索机制，可能与某些人类脊柱裂病例的发病机制比神经管未能关闭的模型更相关。我们使用组织特异性基因消融来确定个体组织对Noggin的需求，以维持神经形成。我们的初步数据表明，Noggin促进神经管细胞粘附细胞粘附分子，如N-钙粘蛋白。我们的总体假设是，Noggin是必需的封闭缝沿着的背神经管的封闭的维护。我们测试这一点以及替代模型，并评估下游分子和细胞途径。 公共卫生相关性：这项挑战补助金申请使用小鼠模型系统解决脊柱裂的机制。使用遗传学方法，辅以分子和细胞检测，我们剖析了小鼠头蛋白突变体中完全渗透性脊柱裂表型的发育原因。脊柱裂在人类中知之甚少，但在美国每年出生的约400万婴儿中，约有2,000人受到影响。虽然如果手术修复，活产婴儿通常不会致命，但通常会发生终身并发症，平均每个病例的费用超过100万美元。

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.