title: Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1.
abstract: The mammary epithelium is organized as a bilayer of luminal and basal/myoepithelial cells. During pregnancy, the luminal compartment expands for milk production, while basal cells are thought to provide structural and contractile support. Here, we reveal a pregnancy-specific role of basal epithelia as a central coordinator of lactogenesis. We demonstrate that genetic deletion of the transcription factor p63 (Trp63) gene exclusively within basal cells of the adult gland during pregnancy leads to dramatic defects in luminal cell proliferation and differentiation, resulting in lactation failure. This phenotype is explained by direct transcriptional activation of the epidermal growth factor family ligand gene Nrg1 by p63 selectively in basal cells, which is required for luminal ERBB4/STAT5A activation and consequent luminal progenitor cell maturation. Thus, paracrine basal-to-luminal cell signaling, controlled by p63 via NRG1, orchestrates the entire lactation program. Collectively, these findings redefine the paradigm for cellular interactions specifying the functional maturation of the mammary gland.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Forster
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Srinivas Vinod
authors.initials: SV
authors.lastname: Saladi
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maaike
authors.initials: M
authors.lastname: van Bragt
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Sfondouris
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Jones
authors.affiliation: Department of Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA. Electronic address: ellisen@helix.mgh.harvard.edu.
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D007774:Lactation; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology; D051379:Mice; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism; D066247:Receptor, ErbB-4; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D010750:Phosphoproteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4