Members of the well-studied TNF ligand and receptor families are involved in the immune defence system supporting either cell survival and proliferation or promoting apoptosis. Recently new roles have emerged for them during embryogenesis.
TNFs are type II membrane proteins or soluble ligands that share a homologous TNF domain in the extracellular portion of the molecule. There is little sequence homology elsewhere. The ligands can homotrimerise and bind to trimeric TNF receptors via cysteine-rich domains in the extracellular regions of the membrane receptors. In the intracellular portion of the receptors there is no known enzymatic activity, but many of them contain a death domain which is involved in apoptosis or protein-protein interactions. Some receptors bind the TRAF adapter proteins. Downstream signalling is mediated through the signalling pathways NFkB, JNK or p38 (Baker & Reddy, 1996; Inoue et al, 2000). Transcriptional activation of downstream target genes causes apoptosis or cell survival/proliferation. New TNF/TNFR family members which are involved or suspected to be involved in developmental processes are osteoprotegerin-ligand/RANK, ectodysplasin/Edar/XEDAR (Tabby, Downless) and TNFR19 (also called Troy, Taj, or Trade).
Ectodysplasin (Tabby), a TNF ligand, and Edar (downless), a TNF receptor, were the first TNF/TNFR molecules found to be necessary in tooth development (Srivastava et al, 1997; Ferguson et al, 1997; Mikkola et al, 1999; Headon & Overbeek, 1999). Mutations in the mouse genes Tabby and downless produce identical phenotypes with defects in teeth, hair and circa 20 glands, most noticably the sweat glands (Grüneberg, 1965, 1966, 1971, Sofaer, 1969). In humans the corresponding syndromes, X-linked and autosomal ectodermal dysplasias, share a similar phenotype with the mouse mutations (Kere et al, 1996; Monreal et al, 1999).
There are several splicing forms of the Tabby gene (Srivastava et al, 1997; Ferguson et al, 1997; Mikkola et al, 1999). Recently it was discovered that one of these forms, the longest cDNA Ta-A1 (391 aa), specifically binds to the Eda receptor (Edar). However, the second longest cDNA, Ta-A2, which differs from Ta-A1 by only a two-amino acid deletion in the TNF domain, does not bind Edar, but instead binds a novel TNF receptor called XEDAR. XEDAR was cloned based on homology to TNF receptors. It is expressed in the hair follicles somewhat later in development than downless, but its expression pattern in tooth is not known, nor is the mutant phenotype. Both ligand-receptor pairs activate downstream NFB signalling (Yan et al, 2000).
TNFRSF19 is new receptor whose ligand binding domain has the closest homology to Edar. Its ligand is not known. It is expressed is epithelial structures e.g. skin during development in a similar pattern as downless but its expression pattern in tooth has not been studied, and nor has the mutant phenotype (Kojima et al, 2000).