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)翻译科学，以及具体的挑战主题15-NS-106：识别神经系统发育和功能的基础机制。这一挑战征集了阐明神经系统形成原理的机械学研究，以及分析正常机制是如何在神经系统疾病中受到干扰的。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，但其病因仍鲜为人知。我们建议对Noggin突变小鼠腰椎裂的原因进行机制分析。与几乎所有其他神经管缺陷的小鼠品系不同，Noggin的脊柱裂表型并不是由于背侧神经折叠未能闭合成管而发生的。相反，在关闭一天左右后，腰椎脊髓在中线沿线的孤立区域重新背部开放。这导致了腰椎裂的表型。这个突变体代表了一种未知脊柱裂机制的新小鼠模型，与神经管无法关闭的模型相比，这种模型可能与某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维持神经形成所需的个体组织。我们的初步数据表明，Noggin促进神经管细胞与N-钙粘素等细胞黏附分子的黏附。我们的总体假设是，在沿着背侧神经管的闭合缝中，需要Noggin来维持闭合。我们测试了这一点以及其他模型，并评估了下游的分子和细胞途径。 公共卫生相关性：这项挑战奖助金申请使用小鼠模型系统解决脊柱裂的机制。利用遗传学方法，辅以分子和细胞分析，我们剖析了小鼠noggin突变体中完全穿透性脊柱裂表型的发育原因(S)。脊柱裂在人类中知之甚少，但在美国每年出生的大约400万婴儿中，约有2000人受到影响。虽然如果通过手术修复，活产婴儿通常不会致命，但终生并发症通常会发生，每个病例的平均成本超过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.