4.5 Article

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

Journal

MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 9, Pages 1543-1556

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00136-15

Keywords

-

Funding

  1. U.S. National Institutes of Health [DK56621, AA020709, P20AA017067, 1K05AA018408]
  2. NIH/National Cancer Institute [CA109182]
  3. Samuel Waxman Cancer Research Foundation
  4. Astellas Foundation for Research on Metabolic Disorders

Ask authors/readers for more resources

Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1 alpha-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, alpha/beta-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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available