description): The candidate's goals are to become an independent investigator and to pursue a career in academic pediatric cardiology. He will perform research under the guidance of a pediatric cardiologist with expertise in the field of cardiovascular development. While in the laboratory, he will acquire new skills in molecular biology and have access to state-of-the-art facilities. The candidate will be in a Pediatric Department that has afforded him protected research time during his fellowship. He is at a university where he will have contact with professors with extensive backgrounds in molecular and developmental biology, and that hosts lectures from eminent basic scientists from around the world. The long term objectives of the research project are to determine the role of UFD1 and CDC45 in neural crest cells during embryogenesis. Neural crest cells are involved in cardiac development, as they are important for the normal formation of the cardiac outflow tract and aortic arch arteries. The CATCH-22 (gardiac defects, abnormal facies, !hymic hypoplasia, cleft palate, and itypocalcemia associated with chromosome 22 microdeletion) syndrome is believed to arise from neural crest defects. The CATCH-22 syndrome is the most common human genetic deletion with an incidence of 1/4,000 live births and is the second most common genetic cause of congenital heart disease (CHD). In CATCH-22, 90% of the patients share in common a deletion spanning 2-3 Mb of one copy of chromosome 22q II, but the gene(s) responsible have not been determined. Individuals with CATCH-22 have CHD involving the cardiac outflow tract and aortic arch arteries. UFDl and CDC45 are two of the nearly thirty genes located in the DiGeorge Critical Region (DGCR) on chromosome 22q 11. A patient with the CATCH-22 phenotype was identified who had a monoallelic deletion of the first three exons of the UFDI(ubiquitin fusion degradation protein) gene and the first five exons of a neighboring gene, CDC45 (cell-division-cycle protein). By in situ hybridization, Ufdl and Cdc45 were co-expressed in the neural crest-derived pharyngeal arches, aortic arch arteries, and cardiac outflow tract. Prior to this, HIRA, a transcriptional regulator, was the only other gene in the DGCR specifically expressed in neural crest-derived tissues during embryogenesis.
The specific aims of the project are: I. To determine the function of Ufd 1 and Cdc45 in embryogenesis. 2. To determine the role of Cdc45 in neural crest development. 3. To determine if protein-protein interactions exist between Ufdl, Cdc45, and Hira. A conventional knockout strategy will be used to delete the Ufdl and Cdc45 genes in mice. Heterozygous and homozygous mice will be analyzed for neural crest defects. The function of Cdc45 will be examined in vivo in chick embryos by retrovirally mediated alteration of gene expression. A yeast two hybrid assay will be utilized to determine if Ufdl, Cdc45, and Hira interact with one another.
| Garg, V; Yamagishi, C; Hu, T et al. (2001) Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic hedgehog during pharyngeal arch development. Dev Biol 235:62-73 |
| Kunte, A; Ivey, K; Yamagishi, C et al. (2001) A common cis-acting sequence in the DiGeorge critical region regulates bi-directional transcription of UFD1L and CDC45L. Mech Dev 108:81-92 |
