Genetic Pathways of Hair Medulla Differentiation-Paradigms for Development

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DESCRIPTION (provided by applicant): Skin and hair are obvious external features that directly reflect an individuals' health condition. Genes that regulate normal development and function of the skin often play critical roles in other organ systems. While there is much focus on skin and hair follicle cycling and development, very little is known about the formation of the hair medulla. We recently determined that the transcriptional regulator Hoxc13 plays a key role in hair follicle differentiation, including the formation of the medulla, where it is involved in the control of other regulatory genes (Foxql, Foxnl, Junb), as well as structural genes (Crispl, Krt2-16, Dsc2). All of these genes have been implicated in a host of abnormalities in tissues other than hair. Our overall hypothesis is that using the hair follicle medulla as a model for defining functional regulatory networks including these genes will be of great relevance for understanding complex disease mechanisms involving mutations or dysregulation of the same genes. Aim1: We will begin by investigating the hair interior defect (hid) mutation, which affects medulla formation and appears to be linked to a novel gene. Having mapped the hid mutation recently to mouse chromosome 1, we will localize it further by high-resolution mapping to identify the corresponding gene and characterize its expression pattern. Aim2: To define the genetic pathways of medulla differentiation involving hid, a multi-step approach will utilize cross-examination of expression patterns of genes associated with medulla differentiation in a panel of corresponding hair medulla mutant mice including hid by in situ hybridization j and real-time quantitative PCR. Individual pathway predictions will be tested in subsequent steps by generating compound mutants and in vitro DMA binding assays. Dissecting the regulatory circuitry controlling hair medulla formation will significantly contribute to understanding the mechanisms underlying diseases not only of the hair and skin but of many other organ systems as well.