title: SLIT/ROBO1 signaling suppresses mammary branching morphogenesis by limiting basal cell number.
abstract: In the field of breast biology, there is a growing appreciation for the "gatekeeping function" of basal cells during development and disease processes yet mechanisms regulating the generation of these cells are poorly understood. Here, we report that the proliferation of basal cells is controlled by SLIT/ROBO1 signaling and that production of these cells regulates outgrowth of mammary branches. We identify the negative regulator TGF-β1 upstream of Robo1 and show that it induces Robo1 expression specifically in the basal layer, functioning together with SLIT2 to restrict branch formation. Loss of SLIT/ROBO1 signaling in this layer alone results in precocious branching due to a surplus of basal cells. SLIT2 limits basal cell proliferation by inhibiting canonical WNT signaling, increasing the cytoplasmic and membrane pools of β-catenin at the expense of its nuclear pool. Together, our studies provide mechanistic insight into how specification of basal cell number influences branching morphogenesis.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, 95064, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Macias
authors.forename: Angel
authors.initials: A
authors.lastname: Moran
authors.forename: Yazeed
authors.initials: Y
authors.lastname: Samara
authors.forename: Melissa
authors.initials: M
authors.lastname: Moreno
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Compton
authors.forename: Gwyndolen
authors.initials: G
authors.lastname: Harburg
authors.forename: Phyllis
authors.initials: P
authors.lastname: Strickland
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
mesh_terms: D000818:Animals; D060466:Axin Protein; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000502:physiology; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D060466:Axin Protein; D003598:Cytoskeletal Proteins; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D051176:beta Catenin; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C111729:Axin2 protein, mouse; C120010:Slit1 protein, mouse; C432251:Slit3 protein, mouse; C090140:Whn protein