Disease relevance of Eda

• X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands [1].
• A new radiation-induced mutation in the mouse, tabby-25H (Ta25H), has proved to be a deletion which spans both the tabby and testicular feminization (Tfm) loci on the X chromosome [2].
• Studies in 25 epidermal growth factor (EGF)-treated mutants and 23 saline-treated controls showed that neonatal EGF injections (4 micrograms g-1 body weight per day) reversed the delayed timing of eyelid opening and incisor eruption in hemizygote and homozygote Tabby mice [3].
• This study investigated relationships between the skin abnormalities of Ta mice and the EGF signal pathway [4].
• In mice, lack of Eda leads to failure in primary hair placode formation and missing or abnormally shaped teeth, whereas mice overexpressing Eda are characterized by enlarged hair placodes and supernumerary teeth and mammary glands [5].

High impact information on Eda

• We show that beta-catenin is required genetically downstream of tabby/downless and upstream of bmp and shh in placode formation [6].
• Here, we show that treatment of pregnant Tabby mice with a recombinant form of EDA1, engineered to cross the placental barrier, permanently rescues the Tabby phenotype in the offspring [7].
• We now report that EGF induces development of dermal ridges and functional sweat glands in Ta/Y hemizygotes, indicating a role in mammalian morphogenesis [8].
• Both sequences map to the region of 10 centimorgan lying between the Tabby (Ta) and St14-1 (DxPas8) loci, close to the phosphorylase b kinase locus (Phk) [9].
• Three of the probes map to the region between the centromere and Hprt, and two distal to Ta [10].

Chemical compound and disease context of Eda

• The convulsant properties of methyl beta-carboline-3-carboxylate (beta-CCM) were evaluated in the TaT-fm/GncTa+/+Tfm strain carrying the tabby coat color (Ta) and/or the testicular feminization (Tfm) gene [11].

Biological context of Eda

• As predicted by the similarity in adult mutant phenotype and the structure of the proteins, we demonstrate that Eda and Edar specifically interact in vitro [12].
• Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis [12].
• Five probes localizing to the Xq26-Xqter region of the human X chromosome have been genetically mapped on the mouse X chromosome using an interspecific cross involving Mus spretus to a contiguous region lying proximally to the Tabby (Ta) locus [13].
• As Ta25H/+ females show the striped X-inactivation coat pattern, the putative X-inactivation centre, Xce, which lies close to Ta, cannot be located within the region deleted [2].
• Effect of the X-linked gene Tabby (Ta) on eyelid opening and incisor eruption in neonatal mice is opposite to that of epidermal growth factor [3].

Anatomical context of Eda

• Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles [1].
• By adding a soluble form of Edar to tooth germs, we were able to mimic the tabby enamel knot phenotype, demonstrating the involvement of endogenous Eda in tooth development [12].
• We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes [1].
• Taken together, our results suggest that the Eda/Edar/NF-kappaB pathway exerts its effect on SMG epithelial cell proliferation, lumina formation, and histodifferentiation [14].
• Although recent studies have focused on the role of Eda/Edar signaling during hair and tooth development, very little is known about its role during embryonic submandibular salivary gland (SMG) development [14].

Associations of Eda with chemical compounds

• Ectodysplasin (Eda), a member of the tumor necrosis factor (TNF) superfamily, and its receptor Edar are necessary components of ectodermal organ development [15].
• To analyze their action further, we conditionally expressed the isoforms as tetracycline ('Tet')-regulated transgenes in Tabby (EDA-negative) and wild-type mice [16].
• MATERIALS AND METHODS: Eight-week-old androgen-resistant testicular feminized male (Tfm) and Tabby control mice were orchidectomized (ORX) and treated for 4 weeks with a slow-release testosterone (T) pellet (delivering 167 microg/day) or a placebo pellet [17].
• SETTING AND SAMPLE POPULATION: Institute of Experimental Medicine, Academy of Sciences, Prague. Heads of 75 Ta homozygous and hemizygous mice and 40 wild type (WT) control mice aged from embryonic day (ED) 14.0-20.5 (newborns), harvested during 1995-2001 [18].

Regulatory relationships of Eda

• We now demonstrate that epidermal NF-kappaB activity is first observed in placodes of primary guard hair follicles at day E14.5, and that in vivo NF-kappaB signalling is activated downstream of Eda A1 and EdaR [19].
• Instead FGF-10 partially restored morphogenesis and stimulated the development of additional tooth cusps in cultured Tabby molars [20].

Other interactions of Eda

• Eda supplementation induced a significant increase in SMG branching, and enhanced activation of NF-kappaB [14].
• We have established a Mus spretus/Mus musculus domesticus interspecific backcross segregating for two X-linked mutant genes, Ta and Hyp, using in vitro fertilization [21].
• Interactions between epidermal growth factor and the Tabby mutation in skin [4].
• This high-density map provides probes in the vicinity of a number of important genetic loci in this region which include the X-inactivation center, the Ta locus, and the mottled (Mo) locus, and therefore provides a molecular framework for identification of the genes encoded at these loci [22].
• Glands are completely absent in mice lacking Ectodysplasin (Eda) and Edaradd (Eda receptor adaptor protein), members of the tumor necrosis (TNF) superfamily of signaling factors [23].

Analytical, diagnostic and therapeutic context of Eda

• Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and edar (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer [24].
• To begin to analyze EDA pathways, we have used expression profiling on 15,000-gene mouse cDNA microarrays, comparing adult mouse skin from wild-type, EDA-defective (Tabby) mice, and Tabby mice supplemented with the EDA-A1 isoform, which is sufficient to rescue multiple Tabby phenotypes [25].
• Reverse transcription polymerase chain reaction (RT-PCR) studies detected Zfy in mRNA in testes even when Ta was present [26].
• Unexpectedly, sequence analysis of the most C-terminal domain of Ta revealed that ectodysplasin is a novel member of the tumor necrosis factor (TNF) ligand superfamily [27].
• Northern blotting showed Zfy to be expressed in the testes of XXSxr animals, except for those that carry the coat-marker gene Tabby (Ta), despite the lack of germ cells in XXSxr mice [26].

References