Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression

Abstract

Ectodermal organogenesis is regulated by inductive and reciprocal signalling cascades that involve multiple signal molecules in several conserved families. Ectodysplasin-A (Eda), a tumour necrosis factor-like signalling molecule, and its receptor Edar are required for the development of a number of ectodermal organs in vertebrates. 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. Here, we report two signalling outcomes of the Eda pathway: suppression of bone morphogenetic protein (Bmp) activity and upregulation of sonic hedgehog (Shh) signalling. Recombinant Eda counteracted Bmp4 activity in developing teeth and, importantly, inhibition of BMP activity by exogenous noggin partially restored primary hair placode formation in Eda-deficient skin in vitro, indicating that suppression of Bmp activity was compromised in the absence of Eda. The downstream effects of the Eda pathway are likely to be mediated by transcription factor nuclear factor-B (NF-B), but the transcriptional targets of Edar have remained unknown. Using a quantitative approach, we show in cultured embryonic skin that Eda induced the expression of two Bmp inhibitors, Ccn2/Ctgf (CCN family protein 2/connective tissue growth factor) and follistatin. Moreover, our data indicate that Shh is a likely transcriptional target of Edar, but, unlike noggin, recombinant Shh was unable to rescue primary hair placode formation in Eda-deficient skin explants.

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

“…However, taken together with previous studies showing that treatment of embryonic Eda Ta/Ta skin cultures with recombinant EDA A1 results in up-regulation of Shh (Pummila et al, 2007) and that Shh is down-regulated in Eda Ta/Ta SMGs (Melnick et al, 2009), our results provide strong additional evidence that Shh is an important downstream target of Eda signaling in the SMGs. Eda Ta/Ta mice lack primary hair follicles, yet treatment of Eda Ta/Ta skin cultures with exogenous Shh does not rescue their initiation (Pummila et al, 2007), consistent with a later role for Shh in skin appendage development. In some cases, however, Shh overexpression is associated with tumor formation in the skin (Oro et al, 1997).…”

“…Recombinant Shh-N Rescues Branching in Edar dlJ/dlJ SMGs In Vitro qPCR profiling has revealed downregulation of Shh in Eda Ta/Ta SMGs in comparison with WT SMGs (Melnick et al, 2009), and treatment of embryonic Eda Ta/Ta skin cultures with recombinant EDA A1 results in up-regulation of Shh (Pummila et al, 2007). We hypothesized that application of recombinant Shh to Eda pathway mutant SMGs explants would rescue the branching defect.…”

“…Notably, treatment of embryonic Eda Ta/Ta skin cultures with recombinant EDA A1 results in rapid and significant upregulation of Shh (Pummila et al, 2007). Furthermore, recent quantitative polymerase chain reaction (qPCR) profiling has revealed downregulation of Shh in Eda Ta/Ta SMGs in comparison with WT SMGs (Melnick et al, 2009).…”

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

“…Edar signaling may serve as one of the candidates in mediating the cross talk between BMP and Shh pathways in trichogenic tumors: Edar expression is increased in HF-derived tumors of K14-noggin mice (Figure 2), Edar has been shown to be a direct target for down-regulation by BMP signals, 53 and, in turn, is capable of positively regulating Shh expression. 54 It remains to be further determined whether other regulatory molecules, whose expression is changed in tumors ( Figure 2, see supplemental Tables S1 and S2 at http://ajp.amjpathol.org), are also capable of modulating a cross-talk between the BMP and Shh signaling pathways during the neoplastic process in the HF. Furthermore, potential roles for a large number of genes that show differences in expression between hair matrix of wild-type and tumors in K14-noggin mice (see supplemental Tables S1 and S2 at http://ajp.amjpathol.org) remain to be further defined in terms of their contribution to the development of HF neoplasia in noggin transgenics.…”

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

“…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). In the earliest stages of follicle initiation, there has been an emphasis on determining the molecular factors that distinguish the placode versus the interfollicular epidermis (Nowak et al, 2008;Rhee et al, 2006).…”