This project has two major goals within the program. The first is to determine the relevance of human genes identified in Project 1 and isolated in Project 3 to cranial-facial morphogenesis. This will be accomplished by first isolating the mouse homologues of human genes identified within 22q11. Homology to human genes will be determined by sequence analysis and southern blotting using human/hamster hybrid panels including those carrying human chromosome 22 with the q11.2 microdeletions. The characterized mouse homologue will be used to determine the program and site of expression of candidate genes in the developing mouse embryo. This will be accomplished by RT-PRC amplification and in situ hybridization. The functional significance of any candidate gene to cranial-facial development will be determined by blocking gene expression using anti-sense oligodeoxyribonucleotides administered externally, injected locally or generated intracellularly via viral vectors applied to cultured mouse embryos, and by inappropriate gene expression in transgenic animals. Disruption of cranial-facial formation will be monitored anatomically and immunohistochemically using monoclonal antibodies specific for vascular endothelial cells and neural crest cells to localize specific cells or structures as """"""""land marks"""""""". The second major goal is to independently identify and characterize, as described above, genes expressed during cranial-facial morphogenesis by cranial neural crest cells or within the pharyngeal arches and head region of staged mouse embryos. This will be accomplished by differential comparison of RT-PCR amplified mRNA products on sequencing gels followed by PCR amplification, RACE extension and screening of mouse cDNA libraries to produce probes for functional analysis in developing mouse embryos or cultured cells utilizing the antisense and gene expression strategy described above. Mouse genes expressed in the embryo at a time and place consistent with their being active during cranial- facial morphogenesis will be tested for their ability to hybridize to human 22q11 to determine if they may be murine homologues of genes within this region of the human chromosome. Upon completion of this work we will have determined the functional significance of any new genes expressed during early cranial-facial development in the mouse. These latter genes may rest outside the VCFS critical region. They will however, be important to understanding the complete genetic program required for proper morphogenesis of structures of the head and face affected in VCFS patients.
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