Ectodysplasin signaling via Xedar is required for mammary gland morphogenesis

ABSTRACT The Ectodysplasin A2 receptor (XEDAR), is a member of the tumor necrosis factor receptor subfamily and is a mediator of the Ectodysplasin (EDA) signaling pathway. EDA signaling plays evolutionarily conserved roles in the development of the ectodermal appendage organ class that includes hair, eccrine sweat glands, and mammary glands. Loss of function mutations in Eda , which encodes the two major ligand isoforms, EDA-A1 and EDA-A2, result in X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by defects in two or more ectodermal appendage types. EDA-A1 and EDA-A2 signal through the receptors EDAR and XEDAR, respectively. While the contributions of the EDA-A1/EDAR signaling pathway to ectodermal appendage phenotypes have been extensively characterized, the significance of the EDA-A2/XEDAR branch of the pathway has remained obscure. Herein, we report the phenotypic consequences of disrupting the EDA-A2/XEDAR pathway on mammary gland differentiation and growth. Using a mouse Xedar knock-out model, we show that Xedar has a specific and temporally restricted role in promoting post-pubertal growth and branching of the mammary epithelium that can be influenced by genetic background. Our findings are the first to implicate Xedar in ectodermal appendage development and suggest that the EDA-A2/XEDAR signaling axis contributes to the etiology of EDA -dependent mammary phenotypes.