Roles of Ovol genes in mouse epidermal development

The Ovo gene family encodes a group of transcriptional factors containing a conserved zinc-finger domain that are conserved through evolution and Ovo members have been shown to be downstream targets of important developmental pathways such as Wnt and TGF-beta. In this thesis, the function of Ovol1, the first characterized Ovo gene in mouse, and its genetic interaction with Ovol2 during epidermal development is explored. Ovol1 had been shown to express in the suprabasal layers of the epidermis, however, Ovol1 knockout mice in a mixed genetic background (129Sv X C57BL/6) showed no defects in skin development. When transferred the Ovol1 mutant allele into a complete C57BL/6 genetic background, a novel function of Ovol1 was discovered in terminal differentiation during epidermal development. In B6-enriched Ovol1 knockout embryo skin, a mild-hyperplasia was observed and this observation led to the discovery of Ovol1's function in regulating cell cycle arrest during terminal differentiation. Biochemical studies also revealed that Ovol1 executes its function in cell cycle arrest by regulating c-myc and Id2, two genes that are known to play a role in proliferation. In addition, Ovol1 regulates the terminal differentiation by regulating the expression of loricrin, a late terminal differentiating protein and an important component for the formation of cornified envelope of epidermal barrier function.; B6-Ovol1 mutant mice also exhibited partial perinatal lethality and the causes of death might be a weaken skin barrier or kidney defects. Genetic analysis using Ovol1/Ovol2 compound heterozygous mutants revealed that Ovol2 plays a compensatory role for Ovol1 in the perinatal lethality phenotype that was observed in B6-Ovol1 single mutant. Further analysis using an in vitro binding assay and reporter assay had revealed that Ovol1 protein directly regulates the expression of Ovol2. This works has also shown that Ovol2 protein is expressed in the basal layer of the epidermis, suggesting a possible function of Ovol2 to play in proliferation in epidermal development. These findings provide some preliminary evidence for the requirement of Ovol2 in skin development and lay a foundation for future study of Ovol2 function; however, a skin specific knockout of Ovol2 is required to dissect out the exact function of Ovol2 in skin, since Ovol2 complete knockout died at an early embryonic stage.