Role of Ectodysplasin-A in Skin Appendages Formation

Schlessinger, David

Abstract

Of more than 175 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. Analysis of the promoter region has revealed transcription elements that include enhancers, possibly implicated in the tissue specificity of the gene; they include sites that implicate the wnt and EGF pathways. With our collaborators, we had 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. Now a first transgenic mouse, which incorporates one of the 8 isoforms of the protein, partially rescues the Tabby phenotypes. This provides an experimental system to study the gene function systematically during embryonic development.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AG000643-03
• Application #: 6431438
• Study Section: (LG)
• Support Year: 3
• Fiscal Year: 2000

Institution

• Name: Aging
• Country: United States

Publications

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