Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages

Abstract

Organs developing as appendages of the ectoderm are initiated from epithelial thickenings called placodes. Their formation is regulated by interactions between the ectoderm and underlying mesenchyme, and several signalling molecules have been implicated as activators or inhibitors of placode formation. Ectodysplasin (Eda) is a unique signalling molecule in the tumour necrosis factor family that, together with its receptor Edar, is necessary for normal development of ectodermal organs both in humans and mice. We have shown previously that overexpression of the Eda-A1 isoform in transgenic mice stimulates the formation of several ectodermal organs. In the present study, we have analysed the formation and morphology of placodes using in vivo and in vitro models in which both the timing and amount of Eda-A1 applied could be varied. The hair and tooth placodes of K14-Eda-A1transgenic embryos were enlarged, and extra placodes developed from the dental lamina and mammary line. Exposure of embryonic skin to Eda-A1 recombinant protein in vitro stimulated the growth and fusion of placodes. However, it did not accelerate the initiation of the first wave of hair follicles giving rise to the guard hairs. Hence, the function of Eda-A1 appears to be downstream of the primary inductive signal required for placode initiation during skin patterning. Analysis of BrdU incorporation indicated that the formation of the epithelial thickening in early placodes does not involve increased cell proliferation and also that the positive effect of Eda-A1 on placode expansion is not a result of increased cell proliferation. Taken together, our results suggest that Eda-A1 signalling promotes placodal cell fate during early development of ectodermal organs.

Recombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitro

“…Injection of a recombinant form of EDA A1 given to pregnant Eda Ta/ Ta mice in a series beginning at E11 leads to the almost complete rescue of the organs affected in the developing embryos (Gaide and Schneider, 2003), although the effect on the SGs was not documented. In vitro, supplementation of Eda Ta/Ta skin cultures with recombinant EDA A1 rescues hair placode development (Mustonen et al, 2004), while EDA A1 addition to WT SMG cultures increases branching and enhances NFkB activation (Jaskoll et al, 2003). It follows that it may be possible to rescue Eda Ta/Ta SMGs in culture by recombinant EDA A1 supplementation, and here we show that this is achievable during both early and later branching morphogenesis, an encouraging finding for future attempts to correct SG defects in HED patients.…”

“…Recombinant EDA A1 supplementation rescues primary hair follicle development in Eda Ta/Ta skin explants (Mustonen et al, 2004). We attempted to rescue the branching defect identified in embryonic Eda Ta/Ta and Eda Ta/þ SMGs by EDA A1 supplementation in vitro.…”

“…E13.5 SMGs were initially selected because this stage precedes the appearance of the branching defect. We chose to supplement the glands with 100 ng/ml EDA A1 because this concentration rescues primary hair placode development in Eda Ta/Ta skin in vitro (Mustonen et al, 2004).…”

“…Dorsal skin explants from E13.5 Eda Ta/Ta embryos were treated with EDA A1 for 24 hr to rescue primary hair placodes, which do not develop in Eda Ta/Ta (Mustonen et al, 2004;Mou et al, 2006). While primary hair placodes, as detected by Shh expression, remained absent in untreated Eda Ta/Ta skin, rescued placodes were detected in EDA A1-treated Eda Ta/Ta skins (Supp.…”

Evolved tooth gain in sticklebacks is associated with acis-regulatory allele ofBmp6

“…For example, the large-effect toothspacing QTL on chromosome 4 overlaps the Ectodysplasin (Eda) gene which controls adaptive reductions in armor plate patterning (36) and is also well known to affect vertebrate tooth patterning (37,38). Interestingly, Eda also plays a role in the spacing of hair placodes and tooth cusps in mice (39,40), making Eda an excellent candidate for underlying the tooth-spacing QTL on chromosome 4. A third possibility is that some or all of these tooth traits could be changing due to genetic drift occurring after freshwater colonization.…”