DEVELOPMENTAL GENETICS OF NEURAL TUBE FORMATION

本研究将探讨基因互作在小鼠神经管中的作用 发展 神经管的形成是最早的， 哺乳动物胚胎发生中的关键事件以及该过程中的缺陷 （包括遗传缺陷）是人类最常见的出生缺陷之一。 这项研究将利用三种新诱导的小鼠突变， 分离的基础上，他们的相互作用与基因座已知影响 神经管发育 这些新的突变体将被描述为 在遗传和发育上，决定了它们的形态效应， 胚胎和它们对其他神经管突变的修饰 已经描述过了。 研究将包括连锁和映射，组织学 胚胎分析、双突变体的构建和 致命阶段 新的突变体被分离出来，因为它们与 斑点基因座，它导致神经管关闭失败， 纯合条件，和融合，产生重复的神经 管中纯合子。 对新的相互作用位点的研究将有助于确定 正常神经管所需协调作用基因组 阵 由于许多指导神经管发育的基因可能 介导的细胞相互作用，这将是至关重要的，以建立如果一个突变 缺陷是神经板细胞固有的，或者它是否导致 是由外源性异常细胞相互作用引起的 为了解决 这个问题，我们将通过聚合突变体构建遗传嵌合体， 野生型胚胎 细胞的基因型将用新的 分子标记，将细菌β-半乳糖苷酶置于 真核启动子的控制，其将被引入到 正常小鼠品系的生殖细胞。 因此，将有可能对 突变体与野生型细胞的分布，使用 切片胚胎。 通过这种方式，可以进行相关性 细胞必须携带特定的突变，以产生突变体 表型，定义给定突变的细胞作用位点。 这 这项技术将被用来绘制各种遗传和组织的贡献， 神经管的发育，以及追踪细胞谱系的 神经管 从长远来看，这类研究将确定所需的基因组 为神经管的形成奠定了基础， 这个过程

This study will probe the role of gene interactions in mouse neural tube development. Formation of the neural tube is one of the first, most critical events in mammalian embryogenesis, and defects in the process (including genetic ones) are among the most common human birth defects. The study will make use of three newly induced mutations in the mouse, isolated on the basis of their interactions with loci known to affect neural tube development. These new mutants will be characterized genetically and developmentally, determining their morphological effects in embryos and the modifications they impose on other neural tube mutations already described. Studies will include linkage and mapping, histological analysis of embryos, construction of double mutants and determination of lethal phases. The new mutants were isolated for their interactions with the Splotch locus, which causes failure of neural tube closure in homozygous condition, and Fused, which produces duplications of the neural tube in homozygotes. The study of new interacting loci will help define the set of genes whose coordinate action is required for normal neural tube formation. Since many of the genes that direct neural tube development are likely to mediate cell interactions, it will be essential to establish if a mutant defect is intrinsic to cells of the neural plate, or whether it results from an abnormal cell interaction of extrinsic origin. In order to address this question, we will construct genetic mosaics by aggregating mutant and wild-type embryos. The cells' genotypes will be scored with a new molecular marker, a gene fusion placing bacterial Beta-galactosidase under the control of a eukaryotic promoter, which will be introduced into the germ line of a normal mouse strain. Thus, it will be possible to score the distribution of mutant vs. wild-type cells, using antibody staining of sectioned embryos. In this manner, a correlation can be made as to which cells must carry a particular mutation in order to produce the mutant phenotype, defining the cellular site of action of a given mutation. This technique will be used to map the various genetic and tissue contributions to neural tube development, as well as to trace the cell lineage of the neural tube. In the long run, studies of this sort will define the set of genes required for neural tube formation and lay the foundations for molecular studies of this process.