Our long-term goal is to understand transcriptional control mechanisms that underlie development and homeostasis of epidermis and hair follicles. Clim/Nli/Ldb transcriptional co-activators were discovered based on their ability to bind to LIM domains of LIM homeodomain factors, thus conferring transcriptional activation by this class of DNA-binding proteins. One member of this family of co-activators, Clim-2, is highly expressed in keratinocytes where it interacts with the LIM only protein, LMO-4, which is expressed in an overlapping manner in epidermis and hair follicles. Blocking Clim action in mouse epidermis leads to hair loss, abnormal hair cycling, and, in older mice, propensity to epidermal wounding. We hypothesize that Clim-2 regulates hair follicles by interacting with DNA-binding proteins by using LMO-4 as an adapter molecule. We have identified one candidate DNA-binding protein in this pathway, a novel mammalian transcription factor homologous to Drosophila NTF-1, which, when mutated in flies leads to a cuticular phenotype.
The specific aims are: (1) to use a transgenic mouse model to understand how Clim co-activators regulate epidermal and hair homeostasis. Specifically, we plan to identify genes regulated by Clims and to elicit the relationship of Clim to signaling pathways known to regulate hair follicle morphogenesis; (2) to use biochemical approaches to test the hypothesis that the association of LMO-4 with mNTF-1 allows the recruitment of Clim-2 co-activators; and (3) to use transgenic mouse models and gene deletion technology to elucidate the epidermal function of the novel transcription factor, mNTF-1, which was cloned based on its ability to interact with LMO-4. These studies should give insight into normal epidermal biology and how disruption of normal transcriptional control mechanisms leads to diseases such as abnormal wound healing and skin cancer.
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