Mammalian hair follicle is an excellent system to study essential cellular processes such as proliferation, differentiation, and morphogenesis. At the present time, little is known about the molecular pathways that operate in hair follicles to govern the formation of hair, an organ that plays important roles in sensation, temperature regulation, and social interaction. The mouse ovo genes appear to be required for the late-stage differentiation with the hair follicles (i.e., hair morphogenesis). Therefore, they provide a useful molecular handle with which to study how proliferative hair follicle cells differentiate into the highly specialized terminal cells of the hair shaft. In this proposal, mice carrying mutations in the movo genes will be generated, and used to dissect the cellular and molecular events that occur during the process of hair formation, and how these events are regulated. There are three specific aims: 1. Characterizing the functions of movo genes in mouse development and physiology, particularly in hair morphogenesis and epidermal differentiation. The hypothesis that movo2 is required for hair morphogenesis will be tested by generating and analyzing mice with a targeted deletion of the movo2 gene. The hypothesis that movo1 and movo2 double knockout mice. Analysis of mutant mice will include a systematic observation and histological studies of tissues that express movo2, with an emphasis on hair and epidermal defects. Morphological and biochemical markers will be examined in the mutant mice to pinpoint the exact nature of the defects in hair and epidermis. 2. Investigating the mechanisms of movo functions I: a lone in regulating gene expression? mOvo proteins are thought to act as transcription factors. The mOvo downstream target genes will be identified and their regulation by the mOvo proteins studied both in vitro and in vivo. The transcriptional regulatory activities of the mOvo proteins will also be characterized. 3. Investigating the mechanisms of movo functions II. a possible role in cytoskeleton and/or cell adhesion? The hypothesis that movo genes carry an additional function in actin cytoskeleton reorganization and/or cell adhesion will be tested by a)examining the effect of movo over-expression or deletion on cytoskeleton/adhesion in mouse keratinocytes, and b) examining the effect of movo over-expression or deletion on these cellular processes in the knockout and transgenic mice with abnormal levels of movo gene products.
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