Ectodysplasin Signaling through XEDAR Is Required for Mammary Gland Morphogenesis.

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

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer.

Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of BRAFV600E is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status.