title: 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.
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hasegawa
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Calvo
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Avivar-Valderas
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Abigale
authors.initials: A
authors.lastname: Lade
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Chou
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Youngmin A
authors.initials: YA
authors.lastname: Lee
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Farias
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, and Department of Otolaryngology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA scott.friedman@mssm.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D011388:Prolactin / Q000032:analysis / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000032:analysis / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D050799:STAT5 Transcription Factor / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D011388:Prolactin; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4