GENETIC ANALYSIS OF HUMAN BRAIN DEVELOPMENT

人类大脑在早期胚胎发育过程中的发育已经被研究。 主要是描述性的。基因和基因产物的分析 对于中枢神经系统的形态发生来说是必要的 不仅有助于我们理解正常的大脑发育，而且 先天性脑畸形形成的病因学 反常现象。早期胚胎脑形成相关基因的分离 可以通过对个体细胞的分子研究来实现 大脑发育异常。 前脑完整(HPE)序列就是这样一种结构异常 以大脑和面部的中线发育异常为特征的。这个 临床谱系被很好地描述，从严重的形式与 与出生后不相容的单脑室和睫状视 生活，到精神发育迟滞和其他疾病患者的温和形式 发育障碍。全前脑畸形的遗传学基础是 既有家族史又有散发性病例的异质性 特殊的染色体异常。 提出了一系列相关的假设：第一，正常大脑的基因 发育位于优先相关的染色体区域 全前脑畸形。第二，基因安排，例如易位或 基因缺失，改变基因表达，导致临床表现 全前脑序列。第三，这些基因的表达被认为是 最早发生在原肠胚和神经胚期。 胚胎发育第三周。 为了解决这些假设，拟议的研究将集中在一个 与一条新发现的染色体相关的全前脑畸形 7q36中的T(7；9)易位断裂点和多个缺失 包含此断点。1.来自7q36区域的DNA标记将是 已本地化，以生成HPE断点周围的详细物理地图。 2.此断点及其周围的探测将用于识别大型 将人类DNA片段克隆到酵母人工染色体(YAC)中。 3.可获得的小鼠早期胚胎和人胚胎的cdna文库 将用来自HPE的YAC筛选脑特异的cDNA文库 断点区域。4.从这些文库中克隆到HPE 7q36中的断裂点是正常大脑所必需的基因的候选 发展。将对该基因的表达和功能进行分析 为了更好地了解人类正常的大脑结构， 最后，阐明了导致其异常的基本DNA缺陷 全前脑畸形的发育。

Development of the human brain during early embryogenesis has been studied mostly on a descriptive level. Analysis of genes and gene produets necessary for the morphogenesis of the central nervous system will contribute to our understanding not only of normal brain development, but also of the etiology of abnormal formation as seen in congenital brain anomalies. Isolation of genes involved in early embryonic brain formation can be accomplished through molecular studies of cells from individuals with abnormal brain development. The holoprosencephaly (HPE) sequence is such a structural anomaly characterized by abnormal midline development of the brain and face. The clinical spectrum is well described, varying from severe forms with a single brain ventricle and cyclopia, which are incompatible with postnatal life, to milder forms in patients with mental retardation and other developmental disabilities. The genetic basis of holoprosencephaly is heterogeneous with both familial occurrence and sporadic cases due to specific chromosome anomalies. A set of related hypotheses are proposed: First, genes for normal brain development are located in chromosomal regions preferentially associated with holoprosencephaly. Second, gene arrangements, e.g. translocations or deletions, alter gene expression, leading to the clinical features of the holoprosencephaly sequence. Third, expression of these genes is assumed to occur as early as during the gastrulation and neurulation stages in the third week of embryogenesis. To address these hypotheses the proposed research will concentrate on one form of holoprosencephaly associated with a newly identified chromosomal t(7;9) translocation breakpoint in 7q36 and a number of deletions encompassing this breakpoint. 1. DNA markers from the 7q36 region will be localized to generate a detailed physical map around the HPE breakpoint. 2. Probes in and around this breakpoint will be used to identify large fragments of human DNA cloned into yeast artificial chromosomes (YACs). 3. Available cDNA libraries from early mouse embryos and human fetal brain-specific cDNA libraries will be screened with YACs from the HPE breakpoint region. 4. cDNA clones from these libraries that map to the HPE breakpoint in 7q36 are candidates for a gene necessary for normal brain development. Analysis of expression and function of this gene will result in a better understanding of normal brain formation in humans and, ultimately, elucidate the basic DNA defect which programs its abnormal development as seen in holoprosencephaly.