Repertoire of mouse ectodysplasin-A (EDA-A) isoforms

Abstract

Mutations in ectodysplasin-A (EDA) cause loss of hair, sweat glands, and teeth in man and mouse. Isoform EDA-A1 protein shows partial rescue of the affected Tabby mouse phenotypes, suggesting that other isoforms may be required for full function. We describe genomic structure for five EDA isoforms, EDA-A1', A5, A5', A6, and A6', in addition to the previously known EDA-A1, A2, A3, and A4. The novel isoforms together account for approximately 12% of total EDA transcripts. The most different, EDA-A6 and A6', which lack the critical domain for interaction with NF-kappaB-activating receptors, were nevertheless confirmed to be present in mouse and human skin tissue. Other isoforms, EDA-A5 and A5', for example, activated NF-kappaB through receptors EDAR and XEDAR. These properties make new isoforms candidates for modulators of EDA function.

EDA Signaling and Skin Appendage Development

“…41 Recently we recovered a total of 9 Eda-A isoforms from mouse keratinocytes. 42 As predicted, A1 and A2 isoforms predominate, comprising about 80% of the total. 42 The A2 isoform is only 2 amino acids shorter than A1, but binds to a different receptor, XEDAR, which also can activate NFkB mediated transcription in vitro.…”

“…42 As predicted, A1 and A2 isoforms predominate, comprising about 80% of the total. 42 The A2 isoform is only 2 amino acids shorter than A1, but binds to a different receptor, XEDAR, which also can activate NFkB mediated transcription in vitro. 34,43 We also found two new isoforms, A5 and A5', which bind to EDAR and XEDAR, respectively, and activate NFkBs in vitro.…”

“…34,43 We also found two new isoforms, A5 and A5', which bind to EDAR and XEDAR, respectively, and activate NFkBs in vitro. 42 Especially 15,45,46 Another EDAR family member, Troy, is also highly expressed in skin appendages. 46,47 To understand Troy function, we generated a mutant mouse strain by ENU mutagenesis (unpublished results).…”

Troy binding to lymphotoxin-α activates NFκB mediated transcription

“…16,17 Although most TNF ligand family members do not bind to Troy, the possible interaction of Troy with lymphotoxins had not been assessed. 14,15 We find that LTα, but not LTβ, is a ligand of Troy, and that LTα-Troy signaling activates NFkB mediated transcription. The signaling was shown to be involved in mesenchyme-epithelium interaction during skin appendage development, though skin appendages were essentially normal in Troy-defective mice.…”

“…12,13 Troy thus mediates multiple signaling cascades, but unlike EDAR and XEDAR, the ligand that binds to Troy to initiate signaling is still unknown in all systems studied. 14,15 In an effort to find a Troy ligand and assess its function in skin appendage development, we were motivated by our earlier finding that a lymphotoxin-β is involved in hair shaft formation and skin periderm differentiation. 16,17 Although most TNF ligand family members do not bind to Troy, the possible interaction of Troy with lymphotoxins had not been assessed.…”