Ectodysplasin, a protein required for epithelial morphogenesis, is a novelTNF homologue and promotes cell-matrix adhesion

In the mouse Tabby (Ta) mutant and human X-linked anhidrotic ectodermal dys plasia (EDA) syndrome development of several ectodermal organs such as hair , teeth, and sweat glands is impaired. The gene behind Tabby and EDA has be en cloned, and several alternative transcripts have been isolated. The prot ein product named ectodysplasin had no obvious function or prominent homolo gy to other known gene products apart from a short collagen-like sequence. We have isolated two novel Ta transcripts which are Variants of the longest isoform of Tabby, named Ta-A. In situ hybridizations revealed Ta-A to be t he major transcript in the developing embryo. It was detected in the endode rm of early embryos and subsequently in specific locations in the neuroepit helium and ectoderm. Unexpectedly, sequence analysis of the most C-terminal domain of Ta revealed that ectodysplasin is a novel member of the tumor ne crosis factor (TNF) ligand superfamily. Mouse ectodysplasin was biochemical ly and functionally characterized, and shown to be a glycosylated, oligomer ic type II membrane protein (N-terminus inside), all characteristics typica l to TNF-like proteins. Members of the TNF family are critically involved i n host defence and immune response often mediating either apoptosis or cell survival. Expression of Ta in several epithelial cell lines did not result in prominent changes in cell morphology and did not promote apoptosis. Ins tead, it was shown to promote cell adhesion to extracellular matrix, a func tion consistent with its postulated role in epithelial-mesenchymal interact ions regulating the development of ectodermal appendages. Ectodysplasin is the first TNF-like signaling molecule described known to be required for ep ithelial morphogenesis. (C) 1999 Elsevier Science Ireland Ltd. All rights r eserved.