Rankl Impairs Lactogenic Differentiation Through Inhibition of the Prolactin/Stat5 Pathway at Midgestation

Stem Cells. 2016 Apr;34(4):1027-39. doi: 10.1002/stem.2271. Epub 2016 Jan 13.


Prolactin and progesterone both orchestrate the proliferation and differentiation of the mammary gland during gestation. Differentiation of milk secreting alveoli depends on the presence of prolactin receptor, the downstream Jak2-Stat5 pathway and the transcription factor Elf5. A strict regulation of Rank signaling is essential for the differentiation of the mammary gland and in particular for alveolar commitment. Impaired alveologenesis and lactation failure are observed in both, knockout and Rank overexpressing mice; however, the underlying molecular mechanism responsible for these phenotypes remains largely unknown. Using genome-wide expression analyses and functional studies, we show here that Rankl (RL) exposure leads to impaired secretory differentiation of alveolar cells not only in MMTV-RANK but also in wild-type (WT) mammary acini. Conversely, pharmacological blockage of Rank signaling at midgestation in WT mice leads to precocious and exacerbated lactogenesis. Mechanistically, RL negatively regulates Stat5 phosphorylation and Elf5 expression at the onset of lactogenesis. Continuous RL exposure leads to the expansion of basal and bipotent cells in WT and MMTV-RANK acini. Overall, we demonstrate that enhanced Rank signaling impairs secretory differentiation during pregnancy by inhibition of the prolactin/p-Stat5 pathway.

Keywords: Mammary alveoli; Progesterone; Prolactin; Rank; Rankl; p-Stat5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Proliferation / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Expression Regulation, Developmental
  • Janus Kinase 2 / biosynthesis
  • Janus Kinase 2 / genetics
  • Lactation / genetics
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism
  • Mice
  • Mice, Knockout
  • Pregnancy
  • Progesterone / genetics
  • Progesterone / metabolism
  • Prolactin / genetics*
  • Prolactin / metabolism
  • RANK Ligand / biosynthesis
  • RANK Ligand / genetics*
  • STAT5 Transcription Factor / biosynthesis
  • STAT5 Transcription Factor / genetics*
  • Signal Transduction
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • Elf5 protein, mouse
  • RANK Ligand
  • STAT5 Transcription Factor
  • Tnfsf11 protein, mouse
  • Transcription Factors
  • Progesterone
  • Prolactin
  • Jak2 protein, mouse
  • Janus Kinase 2