title: Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC.
abstract: Tissue homeostasis requires somatic stem cell maintenance; however, mechanisms regulating this process during organogenesis are not well understood. Here, we identify asymmetrically renewing basal and luminal stem cells in the mammary end bud. We demonstrate that SLIT2/ROBO1 signaling regulates the choice between self-renewing asymmetric cell divisions (ACDs) and expansive symmetric cell divisions (SCDs) by governing Inscuteable (mInsc), a key member of the spindle orientation machinery, through the transcription factor Snail (SNAI1). Loss of SLIT2/ROBO1 signaling increases SNAI1 in the nucleus. Overexpression of SNAI1 increases mInsc expression, an effect that is inhibited by SLIT2 treatment. Increased mInsc does not change cell proliferation in the mammary gland (MG) but instead causes more basal cap cells to divide via SCD, at the expense of ACD, leading to more stem cells and larger outgrowths. Together, our studies provide insight into how the number of mammary stem cells is regulated by the extracellular cue SLIT2.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Mimmi S
authors.initials: MS
authors.lastname: Ballard
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Iwai
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Department of Biology, California State University Channel Islands, Camarillo, CA 93012, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Stensrud
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Mapps
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Maira Pia
authors.initials: MP
authors.lastname: Postiglione
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Knoblich
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. Electronic address: lhinck@ucsc.edu.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinck
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology* / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D018797:Cell Cycle Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; C561632:inscuteable protein, mouse
keywords: Inscuteable; ROBO; SLIT; SNAIL; asymmetric cell division; breast; mammary stem cell