Zic3 and the Control of Body Pattern Formation

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DESCRIPTION (provided by applicant) The candidate, a board eligible pediatrician with a Ph.D. in molecular genetics, is pursuing a fellowship in genetics. She has a long-standing interest in the mechanisms underlying disease and malformation, especially with regard to the heart. She has pursued relevant clinical and research training with a long term goal of contributing to the understanding of the genetic and molecular mechanisms of human development, particularly cardiac malformation and congenital heart disease. This proposal provides a mechanism for realizing a more immediate career goal of expanding the candidate's research background in gene regulation to the fields of development and embryology, thus combining clinical and research interests. The goal of this proposal is to identify the function of Zic3, a zinc finger transcription factor, in body pattern formation, specifically in mesoderm and left-right axis specification and differentiation. The failure to properly establish body pattern and left-right asymmetry is an important cause of congenital malformation, including complex congenital heart defects. Zic3 is the first gene identified in conjunction with human situs (left-right axis) abnormalities, and the spectrum of anomalies in these individuals is consistent with Zic3 playing a broad role in early embryonic patterning. Investigation of Zic3 function in body patterning will be undertaken via analyses of Zic3 null mutants and transgenic mice over expressing ZIC3 in mesoderm. These mice will be characterized phenotypically and molecularly. By analyzing the effects on the expression pattern of genes known to regulate left-right asymmetry, Zic3 will be placed within the molecular signaling cascade responsible for initiating and maintaining left-right body pattern formation. Misexpression analyses utilizing targeted Zic3 cDNAs with mutations corresponding to those found in human pedigrees will create mouse models of human malformation and allow correlation of phenotype with functional protein domains. Establishing and defining the role of Zic3 in left-right axis formation and mesoderm specification will lead to an improved understanding of embryonic patterning and its importance in human malformation. This proposal will be undertaken in an environment that is renowned for its mouse genetics and developmental embryology, the Department of Molecular and Human Genetics at Baylor College of Medicine. Through a combination of supervised research, scientific interchange, and selected coursework within this environment, the candidate will obtain the training necessary to transition to an independent investigator.