RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1

Purna A. Joshi, Paul D. Waterhouse, Nagarajan Kannan, Swami Narala, Hui Fang, Marco A. Di Grappa, Hartland W. Jackson, Josef M. Penninger, Connie Eaves, Rama Khokha

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35 Scopus citations

Abstract

Systemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mechanisms, we examined mouse models and found that loss of RANK prevents the proliferation of hormone receptor-negative luminal mammary progenitors and basal cells, an accompanying loss of WNT activation, and, hence, a suppression of lobuloalveologenesis. We also show that R-spondin1 is depleted in RANK-null progenitors, and that its exogenous administration rescues key aspects of RANK deficiency by reinstating a WNT response and mammary cell expansion. Our findings point to a novel role of RANK in dictating WNT responsiveness to mediate hormone-induced changes in the growth dynamics of adult mammary cells.

Original languageEnglish (US)
Pages (from-to)31-44
Number of pages14
JournalStem Cell Reports
Volume5
Issue number1
DOIs
StatePublished - Jul 14 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Joshi, P. A., Waterhouse, P. D., Kannan, N., Narala, S., Fang, H., Di Grappa, M. A., Jackson, H. W., Penninger, J. M., Eaves, C., & Khokha, R. (2015). RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1. Stem Cell Reports, 5(1), 31-44. https://doi.org/10.1016/j.stemcr.2015.05.012