Of more than 150 ectodermal dysplasias affecting skin and skin appendages, the X-linked anhidrotic ectodermal dysplasia (EDA) is the only one for which the gene involved has been identified. The gene encodes a protein, which we have named ectodysplasin-A, that has a single transmembrane region and a long, extracellular carboxyterminal tail. Because individuals with EDA have sparse hair, rudimentary teeth, and few sweat glands, the gene is likely involved at an early branch point in the interaction of mesenchyme and embryonic ectoderm during the development of skin appendages. Work in the last year has analyzed the gene and its transcripts, and has begun to give some hints of their mode of action. Analysis of the promoter region has revealed transcription elements that include a new type of enhancer, possibly implicated in the tissue specificity of the gene. Eight different transcripts, all beginning with the same first exon, have been identified. The longest contain a collagen-like repeat, suggesting a role for ectodysplasin-A in cell-cell or cell-matrix interactions. Consistent with this view, transfection of the gene into some types of cells leads to their detachment from substrate. In an additional approach, our collaborators have demonstrated that the Tabby mouse, which has many of the features observed in human EDA, results from the loss of function of the orthologous mouse gene. This provides an experimental system to study the function of the gene in embryonic development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000643-01
Application #
6097859
Study Section
Special Emphasis Panel (LG)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kunisada, Makoto; Cui, Chang-Yi; Piao, Yulan et al. (2009) Requirement for Shh and Fox family genes at different stages in sweat gland development. Hum Mol Genet 18:1769-78
Esibizione, Diana; Cui, Chang-Yi; Schlessinger, David (2008) Candidate EDA targets revealed by expression profiling of primary keratinocytes from Tabby mutant mice. Gene 427:42-6
Nakashima, Eiji; Tran, Joseph R; Welting, Tim J M et al. (2007) Cartilage hair hypoplasia mutations that lead to RMRP promoter inefficiency or RNA transcript instability. Am J Med Genet A 143A:2675-81
Cui, Chang-Yi; Hashimoto, Tsuyoshi; Grivennikov, Sergei I et al. (2006) Ectodysplasin regulates the lymphotoxin-beta pathway for hair differentiation. Proc Natl Acad Sci U S A 103:9142-7
Hashimoto, Tsuyoshi; Cui, Chang-Yi; Schlessinger, David (2006) Repertoire of mouse ectodysplasin-A (EDA-A) isoforms. Gene 371:42-51
Cui, Chang-Yi; Schlessinger, David (2006) EDA signaling and skin appendage development. Cell Cycle 5:2477-83
Cui, Chang-Yi; Smith, Janine A; Schlessinger, David et al. (2005) X-linked anhidrotic ectodermal dysplasia disruption yields a mouse model for ocular surface disease and resultant blindness. Am J Pathol 167:89-95
Cui, Chang-Yi; Durmowicz, Meredith; Ottolenghi, Chris et al. (2003) Inducible mEDA-A1 transgene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles. Hum Mol Genet 12:2931-40
Cui, Chang-Yi; Durmowicz, Meredith; Tanaka, Tetsuya S et al. (2002) EDA targets revealed by skin gene expression profiles of wild-type, Tabby and Tabby EDA-A1 transgenic mice. Hum Mol Genet 11:1763-73
Durmowicz, Meredith C; Cui, Chang Yi; Schlessinger, David (2002) The EDA gene is a target of, but does not regulate Wnt signaling. Gene 285:203-11

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