Genomes and Genes
Zic3 and the Control of Body Pattern Formation
Principal Investigator: STEPHANIE WARE
Abstract: 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.
Funding Period: 2001-08-01 - 2007-07-31
more information: NIH RePORT
- The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryoCanhe Chen
Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
Development 133:319-29. 2006..Our findings indicate that Gdf3 acts in a Nodal-like signaling pathway in pre-gastrulation development, and provide evidence for the functional conservation of Vg1 activity in mice...
- Zic3 is critical for early embryonic patterning during gastrulationStephanie M Ware
Department of Pediatrics, Cincinnati Children s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
Dev Dyn 235:776-85. 2006..At later stages, deficiency of Zic3 results in abnormal mesoderm allocation. These results indicate a requirement for Zic3 during early embryogenesis prior to cardiac and visceral organ patterning...
- Heart defects in X-linked heterotaxy: evidence for a genetic interaction of Zic3 with the nodal signaling pathwayStephanie M Ware
Cincinnati Children s Hospital Medical Center and University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, Ohio, USA
Dev Dyn 235:1631-7. 2006..These studies provide evidence that Zic3 interacts genetically with Nodal in left-right patterning and subsequent cardiac development and delineate a critical Zic3-responsive enhancer required for mediating Nodal expression at the node...
- DNA mutation analysis in heterotaxyStephanie M Ware
Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, OH, USA
Methods Mol Med 126:247-56. 2006..These techniques are applicable to any gene of interest and will be useful for further evaluation of candidate genes for heterotaxy...