DOWNLESS GENE AND ITS ROLE IN INDUCTIVE SIGNALING

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DESCRIPTION: (Adapted from the applicant's abstract) - Inductive interactions between adjacent tissues are important for specification of developmental decisions during normal embryogenesis. There are three mouse mutants, downless, Tabby, and crinkled, that all show identical defects in ectodermal induction of hair follicles, sweat glands, and Meibomian glands. Grafting experiments indicate that these genes are expressed in the ectoderm and that they are required for the ectoderm to be competent to respond to inductive signals from adjacent mesenchymal cells. This proposal is focused on one of these genes, downless. People with the genetic disorder autosomal anhidrotic ectodermal dysplasia (EDA) exhibit defects that are essentially identical to the downless phenotype. A number of years ago, the principal investigator identified insertional mutations in the downless gene; since then he has pursued the positional cloning of this gene and has identified a small 200kb YAC that contains the gene called D9. The YAC has now been used to cure the downless mutation in transgenic mice. In the present proposal, four aims are outlined: 1) To identify and evaluate candidate downless cDNA clones; 2) to identify the recessive dlJ and dominant negative Dlslk mutations and to look for mutations in the homologous gene in human EDA patients; 3) to determine and manipulate the patterns of dl expression during embryonic development, and 4) to identify proteins that interact with the downless protein and to determine whether these are encoded by the Tabby and/or crinkled genes. It is proposed that manipulations of the pattern of downless gene expression in mice will help to define inductive competence and cell fate specification and can be used to assess the feasibility of post-natal sweat gland induction to help prevent hyperthermia in human patients with EDA.