title: Diverse regulation of mammary epithelial growth and branching morphogenesis through noncanonical Wnt signaling.
abstract: The mammary gland consists of an adipose tissue that, in a process called branching morphogenesis, is invaded by a ductal epithelial network comprising basal and luminal epithelial cells. Stem and progenitor cells drive mammary growth, and their proliferation is regulated by multiple extracellular cues. One of the key regulatory pathways for these cells is the β-catenin-dependent, canonical wingless-type MMTV integration site family (WNT) signaling pathway; however, the role of noncanonical WNT signaling within the mammary stem/progenitor system remains elusive. Here, we focused on the noncanonical WNT receptors receptor tyrosine kinase-like orphan receptor 2 (ROR2) and receptor-like tyrosine kinase (RYK) and their activation by WNT5A, one of the hallmark noncanonical WNT ligands, during mammary epithelial growth and branching morphogenesis. We found that WNT5A inhibits mammary branching morphogenesis in vitro and in vivo through the receptor tyrosine kinase ROR2. Unexpectedly, WNT5A was able to enhance mammary epithelial growth, which is in contrast to its next closest relative WNT5B, which potently inhibits mammary stem/progenitor proliferation. We found that RYK, but not ROR2, is necessary for WNT5A-mediated promotion of mammary growth. These findings provide important insight into the biology of noncanonical WNT signaling in adult stem/progenitor cell regulation and development. Future research will determine how these interactions go awry in diseases such as breast cancer.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697.
authors.forename: Kai
authors.initials: K
authors.lastname: Kessenbrock
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064.
authors.forename: Prestina
authors.initials: P
authors.lastname: Smith
authors.affiliation: Department of Anatomy and Biomedical Sciences Program, University of California, San Francisco CA 94143-0452.
authors.forename: Sander Christiaan
authors.initials: SC
authors.lastname: Steenbeek
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pervolarakis
authors.affiliation: Department of Anatomy and Biomedical Sciences Program, University of California, San Francisco CA 94143-0452.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Hyogo, 650-0017, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143-0452.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064; zena.werb@ucsf.edu lhinck@ucsc.edu.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
authors.affiliation: Department of Anatomy and Biomedical Sciences Program, University of California, San Francisco CA 94143-0452; zena.werb@ucsf.edu lhinck@ucsc.edu.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism; D060490:Receptors, Wnt / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D060490:Receptors, Wnt; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C468567:Wnt5b protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse
keywords: epithelial morphogenesis; mammary stem cells; noncanonical Wnt signaling; receptor tyrosine kinase