Involvement of a novel Tnf receptor homologue in hair follicle induction

Abstract

Although inductive interactions are known to be essential for specification of cell fate in many vertebrate tissues, the signals and receptors responsible for transmitting this information remain largely unidentified. Mice with mutations in the downless (dl) gene have defects in hair follicle induction, lack sweat glands and have malformed teeth. These structures originate as ectodermal placodes, which invaginate into the underlying mesenchyme and differentiate to form specific organs. Positional cloning of the dl gene began with identification of the transgenic family OVE1. One branch of the family, dl(OVE1B), carries an approximately 600-kb deletion at the dl locus caused by transgene integration. The mutated locus has been physically mapped in this family, and a 200-kb mouse YAC clone, YAC D9, has been identified and shown to rescue the dl phenotype in the spontaneous dl(Jackson) (dl(J), recessive) and Dl(sleek) (Dl(slk), dominant negative) mutants. Here we report the positional cloning of the dl gene, which encodes a novel member of the tumour necrosis factor (Tnf) receptor (Tnfr) family. The mutant phenotype and dl expression pattern suggests that this gene encodes a receptor that specifies hair follicle fate. Its ligand is likely to be the product of the tabby (Ta) gene, as Ta mutants have a phenotype identical to that of dl mutants and Ta encodes a Tnf-like protein.

NF-κB-related genetic diseases

“…43 The second locus responsible for EDA, called downless in mice, is located on chromosome 2 in humans and accounts for both autosomal recessive and dominant types of the disease. 44,45 It encodes a death-domain containing member of the TNF-R family, EDAR, and is a specific receptor for ectodysplasin. 46,47 Its expression is restricted to placodes, thickenings of epithelia where epidermal appendages begin to form.…”

“…31,47,52 Therefore, mutations in three genes that encode members of a signaling cascade that leads to NF-kB activation result in anhidrotic ectodermal dysplasia. Although the details of the ectodysplasin/EDAR signaling pathway are not fully characterized, it is clear from analyzing the mouse models of EDA pathology that this pathway is involved very early during development of hair follicle morphogenesis, 44 assigning a previously unrecognized role for NF-kB in this process.…”

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

“…In addition to individual follicle morphogenesis, the processes that determine whether surface epithelial cells become interfollicular skin epidermis or HFs also establish the spatial distribution of these appendages. In this context, ectodysplasin A (EDA) and its receptor EDAR appear to play a crucial role (Headon et al, 2001;Headon and Overbeek, 1999;Laurikkala et al, 2002). EDA and EDAR interact with members of the bone morphogenetic protein (BMP) family, some of which are inhibitory to follicle development, to establish follicle patterning (Mou et al, 2006;Pummila et al, 2007).…”

Traf6 is essential for murine tooth cusp morphogenesis

“…The phenotypes of spontaneous mouse mutants tabby, downless, and crinkled are similar to HED and have been found to result from mutations in the same genes as HED. tabby mice carry a mutation in the tumor necrosis factor (TNF) family ligand Ectodysplasin (Eda), downless are mutated in the receptor for Eda (Edar), and crinkled have mutations in an Edar adaptor protein Edaradd (Kere et al, 1996;Headon and Overbeek, 1999;Headon et al, 2001). In tabby, downless, and crinkled mice, molar tooth cusps are rounded and reduced in height (Sofaer, 1969a(Sofaer, ,b, 1977(Sofaer, , 1979Pispa et al, 1999;Tucker et al, 2000;Laurikkala et al, 2001).…”