GENETIC ANALYSIS OF HUMAN BRAIN DEVELOPMENT

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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.