Ectodysplasin/NF-κB Promotes Mammary Cell Fate via Wnt/β-catenin Pathway

Abstract

Mammary gland development commences during embryogenesis with the establishment of a species typical number of mammary primordia on each flank of the embryo. It is thought that mammary cell fate can only be induced along the mammary line, a narrow region of the ventro-lateral skin running from the axilla to the groin. Ectodysplasin (Eda) is a tumor necrosis factor family ligand that regulates morphogenesis of several ectodermal appendages. We have previously shown that transgenic overexpression of Eda (K14-Eda mice) induces formation of supernumerary mammary placodes along the mammary line. Here, we investigate in more detail the role of Eda and its downstream mediator transcription factor NF-κB in mammary cell fate specification. We report that K14-Eda mice harbor accessory mammary glands also in the neck region indicating wider epidermal cell plasticity that previously appreciated. We show that even though NF-κB is not required for formation of endogenous mammary placodes, it is indispensable for the ability of Eda to induce supernumerary placodes. A genome-wide profiling of Eda-induced genes in mammary buds identified several Wnt pathway components as potential transcriptional targets of Eda. Using an ex vivo culture system, we show that suppression of canonical Wnt signalling leads to a dose-dependent inhibition of supernumerary placodes in K14-Eda tissue explants.

Hypohidrotic ectodermal dysplasia: clinical and molecular review

“…Overexpression of EDA increase the size of placodes, while the absence of Edar signaling generates a rudimentary pre‐placode formation . Interestingly, ectopic tooth and mammary placodes and consequently supernumerary organs are induced in mice overexpressing EDA gene . In the case of mammary gland, this is through the ectodysplasin/NF κ B pathway that potentially activates several Wnt pathway components .…”

“…8 Interestingly, ectopic tooth and mammary placodes and consequently supernumerary organs are induced in mice overexpressing EDA gene. 41,42 In the case of mammary gland, this is through the ectodysplasin/NFjB pathway that potentially activates several Wnt pathway components. 42 These data show that in addition to hair follicles, Eda-A1 is also involved in the initiation of mammary glands and tooth development involving different pathways.…”

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

“…As the ligand and receptor were present, we aimed at visualizing Eda pathway activity. For that purpose, we used nuclear factor-kappa B (NF-κB)-gal reporter mice (Bhakar et al, 2002) as a proxy for Eda activity, as previously done in other organs, including mammary gland (Voutilainen et al, 2015), skin (Pispa et al, 2008) and tooth (Ohazama et al, 2004). During LG embryonic development, the Eda pathway was broadly active in both basal and supra-basal cell layers of the epithelial compartment ( Fig.…”

Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects inPax9-/-Mice

“…At least 5 replicates were performed for each assay. For whole-mount X-gal staining of Eda/Edar signaling activity, the whole heads of NF-κB reporter embryos from E12.5 to E15 were fixed in 4% paraformaldehyde after removal of the lower jaw, then treated as previously described (Voutilainen et al 2015).…”

“…Wnt genes encode a family of secreted signaling proteins that regulate developmental processes critical for palatogenesis, such as early patterning, cell proliferation, differentiation, and apoptosis. Several reports confirm that Wnt signaling is linked with the ectodysplasin/ ectodysplasin A receptor (Eda/Edar) pathway during hair follicle, tooth, and mammary gland development (Laurikkala et al 2001;Zhang et al 2009;Voutilainen et al 2015). Since Pax9 is involved with Wnt signaling during palatogenesis, the focus of this study was to evaluate whether the Eda/Edar signaling pathway is involved with Pax9 during palate formation and whether such a relationship could be exploited for pharmacological interventions aimed at correcting palatal defects in Pax9 −/− mice.…”