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Show SPRING 2007 Suzanne Mansour 37 Fgf3 and Fgf4 Have Redundant Functions in the Embryonic Development of the Outer Ear and Vasculature Cameron Jennings (Suzanne Mansour) Department of Human Genetics University of Utah Fibroblast growth factors (FGFs) influence many critical processes in embryonic development including cell proliferation, differentiation, migration, and survival. Fgf3 and Fgf4, which are located contiguously in the mouse and human genomes, are expressed in overlapping and adjacent domains in the developing embryo including the developing head and neck, but their proximity and the fact that Fgf4 homozygous null mutants are dead at implantation (about E4.5), makes it difficult to assess redundant functions. A preliminary study suggested that, mice compound heterozygous for a deletion of Fgf3 and Fgf4 together with the Fgf3Neo allele (Fgf3-4C; Fgf3Neo) showed a lethality rate of near 80% with 63% of survivors having a small outer ear in addition to the deafness and short tail, of the typical Fgf3neo homozygote. It was also reported that E11.5 embryos with this genotype showed hemorrhaging of the left dorsal aorta. Such developmental complications have not been reported in Fgf3Neo or Fgf3C2 homozygous or Fgf3-4C heterozygous mutants, but are remarkably similar to syndromes, including CHARGE and Goldenhar, affecting human patients. Therefore, we propose that Fgf3 and Fgf4 have synergistic functions in development of the external ear and cardiovascular system. The purpose of the proposed research is to determine if Fgf3-4C/Fgf3C mice can serve as a model for cardioauditory syndromes. Phenotypic comparisons between two different Fgf3 alleles, (Fgf3neoand Fgf3A2) will allow us to determine whether any phenotypes observed in compound heterozygotes are solely the result of the absence of Fgf3, or whether the Neo gene, with its regulatory elements may also play a role, perhaps by reducing expression of the downstream Fgf4 gene. Of the 20 offspring from crosses between Fgf3-4C heterozygotes and Fgf3C2 homozygotes, 9 were compound heterozygotes close to the expectation of 10. Crosses between Fgf3-4C and Fgf3Neo heterozygotes! generated 27 mice, only 1 of which was a compound heterozygote. This result is markedly smaller than the expected number of 7, and indicates an increased lethality of the compound heterozygote. Fgf3-4C; Fgf3Neo embryos will be studied at several ages (El 1, E11.5, E12, E12.5, and E13) to determine the time of embryonic death and if and when aortic hemorrhaging occurs. For analysis of embryos, timed pregnant females will be harvested and the embryos will be dissected from the deciduas, injected with India ink to visualize the vasculature, photographed and then prepared for cryosectioning. |