Epithelial Xbp1 Is Required for Cellular Proliferation and Differentiation during Mammary Gland Development

Abstract

Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1α-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, α/β-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00136-15.

ACKNOWLEDGMENTS

We are grateful to Laurie H. Glimcher for the helpful gift of Xbp1^flox/flox mice, Kirsten C. Sadler for critically reading the manuscript, and Rosa Kim, Luke Noon, and Nina Linde for helpful discussions and technical assistance.

This work was supported by U.S. National Institutes of Health grants DK56621, AA020709, P20AA017067, and 1K05AA018408 to S.L.F., NIH/National Cancer Institute grant CA109182 and support from the Samuel Waxman Cancer Research Foundation to J.A.A.-G., and fellowships from the Astellas Foundation for Research on Metabolic Disorders to D.H.

The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript.