title: Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-κB.
abstract: Ductal growth of the mammary gland occurs in two distinct stages. The first round of branching morphogenesis occurs during embryogenesis, and the second round commences at the onset of puberty. Currently, relatively little is known about the genetic networks that control the initial phases of ductal expansion, which, unlike pubertal development, proceeds independent of hormonal input in female mice. Here we identify NF-κB downstream of the TNF-like ligand ectodysplasin (Eda) as a unique regulator of embryonic and prepubertal ductal morphogenesis. Loss of Eda, or inhibition of NF-κB, led to smaller ductal trees with fewer branches. On the other hand, overexpression of Eda caused a dramatic NF-κB-dependent phenotype in both female and male mice characterized by precocious and highly increased ductal growth and branching that correlated with enhanced cell proliferation. We have identified several putative transcriptional target genes of Eda/NF-κB, including PTHrP, Wnt10a, and Wnt10b, as well as Egf family ligands amphiregulin and epigen. We developed a mammary bud culture system that allowed us to manipulate mammary development ex vivo and found that recombinant PTHrP, Wnt3A, and Egf family ligands stimulate embryonic branching morphogenesis, suggesting that these pathways may cooperatively mediate the effects of Eda.
authors.affiliation: Developmental Biology Program, Institute of Biotechnology,  University of Helsinki, 00014 Helsinki,  Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Voutilainen
authors.forename: Päivi H
authors.initials: PH
authors.lastname: Lindfors
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Laura
authors.initials: L
authors.lastname: Ahtiainen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fliniaux
authors.forename: Elisa
authors.initials: E
authors.lastname: Rysti
authors.forename: Marja
authors.initials: M
authors.lastname: Murtoniemi
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
authors.forename: Marja L
authors.initials: ML
authors.lastname: Mikkola
mesh_terms: D066258:Amphiregulin; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066255:EGF Family of Proteins; D053331:Ectodysplasins / Q000378:metabolism*; D047108:Embryonic Development / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D066261:Epigen; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D000728:Androgens; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D053331:Ectodysplasins; C587855:Epgn protein, mouse; D066261:Epigen; D006023:Glycoproteins; D006728:Hormones; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D016328:NF-kappa B; D044162:Parathyroid Hormone-Related Protein; D051153:Wnt Proteins; D004815:Epidermal Growth Factor