Edar and Troy signalling pathways act redundantly to regulate initiation of hair follicle development

Abstract

The development of ectodermal organs requires signalling by ectodysplasin (Eda), a tumor necrosis factor (TNF) family member, its receptor Edar and downstream activation of the nuclear factor kappaB (NF-kappaB) transcription factor. In humans, mutations in the Eda pathway components cause hypohidrotic ectodermal dysplasia, a syndrome characterized by missing teeth, sparse hair and defects in sweat glands. It has been postulated that Eda acts redundantly with another TNF pathway to regulate ectodermal organogenesis. A potential candidate is Troy (or TNFRSF19 or Taj), a TNF receptor which is homologous with Edar in its ligand-binding domain, and is expressed in an overlapping pattern. We have characterized Troy null mice and crossed them with Eda-deficient mice. Single Troy mutants had no defects in ectodermal organs. Analysis of the double mutants revealed an essential role for Troy in hair follicle development. In mice, hair follicles develop in three different waves. Only primary hair follicles are missing in Eda single mutants, whereas the compound mutants lacked also the follicles of the second wave, as well as all hair follicles in the middle of crown leading to focal alopecia. Assessment of NF-kappaB activity with a transgenic reporter construct indicated that Eda is the main activator of NF-kappaB signalling in developing skin appendages and surprisingly that the functional overlap of Troy and Eda signalling pathways is mediated by NF-kappaB independent pathways.

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

“…These data, along with the present work, suggest some redundancy of the pathway. The TNF receptor Troy acts redundantly with Edar in secondary hair follicle development (Pispa et al, 2008) and it would be interesting to investigate the role of Troy in SMG development. We also show that embryonic Eda Ta/Ta and Eda Ta/þ SMGs exhibit a similar branching defect.…”

Ectodysplasin and Wnt pathways are required for salivary gland branching morphogenesis

“…In developing teeth and hair follicles, the effects of Eda are mediated largely by transcription factor nuclear factor-kB (NF-kB) (Schmidt-Ullrich et al, 2001; Pispa et al, 2008). Inhibition of NF-kB in vitro by cell-permeable peptide SN50 was reported to inhibit SMG branching morphogenesis (Melnick et al, 2001a).…”

“…However, more recent studies by the same group (Melnick et al, 2009) suggested that NF-kB activity is not essential for Eda signaling in the salivary gland. To study this obvious discrepancy, we first analyzed NF-kB activity with a NF-kB lacZ reporter mouse (Bhakar et al, 2002;Pispa et al, 2008) in the developing salivary gland. At all stages studied (E12-E17), we observed strong NF-kB signaling activity in the epithelium ( Fig.…”

“…The link between the two pathways is further supported by the conspicuous similarities of individuals carrying mutations in Eda/Edar/Edaradd or in Wnt10a (Adaimy et al, 2007;Cluzeau et al, 2011) (OMIM 257980), which is one of the proposed targets of Edar/NF-kB . Moreover, the transcriptional targets of the two pathways are partially overlapping (Fliniaux et al, 2008;Zhang et al, 2009), and in developing hair, tooth and mammary buds, high Wnt/b-cat and NF-kB signaling activities colocalize in the epithelium (Chu et al, 2004;Liu et al, 2008;Pispa et al, 2008;Zhang et al, 2009). Surprisingly, we did not find a similar correlation between Wnt and NF-kB reporter expression patterns in developing salivary glands, suggesting that unlike in hair follicles, Wnt/ b-cat and Eda/NF-kB may not collaborate in regulation of target gene expression in SMG.…”

Generation and Characterization of Function-blocking Anti-ectodysplasin A (EDA) Monoclonal Antibodies That Induce Ectodermal Dysplasia

“…The EDA1-EDAR axis plays a predominant role in the development of skin-derived structures, whereas EDA2 and XEDAR, also known as EDA2R, have little or no role in this respect (20 -24). XEDAR is closely related to the orphan receptor TROY, and an NF-B-independent role for TROY in hair formation was identified in mice deficient for both TROY and EDA (25). TROY may bind to lymphotoxin ␣ (26), but our laboratory did not detect this interaction (27).…”