Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC

• Published in: Cell reports (Cambridge) Vol. 13; no. 2; pp. 290 - 301
• Main Authors: Ballard, Mimmi S., Zhu, Anna, Iwai, Naomi, Stensrud, Michael, Mapps, Aurelia, Postiglione, Maira Pia, Knoblich, Juergen A., Hinck, Lindsay
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.10.2015; Elsevier
• Subjects: Animals; Asymmetric Cell Division; breast; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Self Renewal; Humans; Inscuteable; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Mammary Glands, Human - cytology; Mammary Glands, Human - growth & development; mammary stem cell; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; ROBO; Roundabout Proteins; Signal Transduction; SLIT; SNAIL; Snail Family Transcription Factors; Stem Cells - cytology; Stem Cells - metabolism; Stem Cells - physiology; Transcription Factors - genetics; Transcription Factors - metabolism; asymmetric cell division; SLIT; Inscuteable; mammary stem cell; ROBO; breast; SNAIL
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.09.006

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. [Display omitted] •Mammary stem cells undergo classic asymmetric cell division•SLIT2/ROBO1 govern stem cell division type by regulating mInsc levels through SNAI1•Excess mINSC drives symmetric cell division•Excess mINSC leads to more stem cells and enhanced mammary outgrowth Tissue homeostasis depends on the balanced self-renewal of stem cells. Ballard et al. describe a mechanism whereby the extracellular cue SLIT2 signals through receptor ROBO1 to regulate the asymmetric self-renewal of basal stem cells during mammary gland development by controlling Inscuteable expression through the transcription factor Snail.