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Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-κB

Item Type:Article
Title:Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-κB
Creators Name:Voutilainen, M. and Lindfors, P.H. and Lefebvre, S. and Ahtiainen, L. and Fliniaux, I. and Rysti, E. and Murtoniemi, M. and Schneider, P. and Schmidt-Ullrich, R. and Mikkola, M.L.
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-kappaB, 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.
Keywords:Hypohidrotic, Ectodermal Dysplasia, Edar, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:109
Number:15
Page Range:5744-5749
Date:10 April 2012
Official Publication:https://doi.org/10.1073/pnas.1110627109
PubMed:View item in PubMed

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