Reciprocal intraepithelial interactions between TP63 and hedgehog signaling regulate quiescence and activation of progenitor elaboration by mammary stem cells

Na Li, Samer Singh, Pratima Cherukuri, Hua Li, Ziqiang Yuan, Leif W. Ellisen, Baolin Wang, David Robbins, James DiRenzo

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

TP63 is required for preservation of epithelial regenerative stasis and regulates the activity of diverse genetic pathways; however, specific effector pathways are poorly understood. Data presented here indicate that reciprocal regulatory interactions between hedgehog signaling and TP63 mediate stage-specific effects on proliferation and clonigenicity of separable enriched mammary stem and progenitor fractions. Analysis of ΔN-p63 and TA-p63 indicates segregated expression in mammary stem and progenitor fractions, respectively, demonstrating that differential TP63 promoter selection occurs during elaboration of mammary progenitors by mammary stem cells. This segregation underlies mammary progenitor-specific expression of Indian Hedgehog, identifying it as a binary transcriptional target of TP63. Hedgehog activation in vivo enhances elaboration of mammary progenitors and decreases label retention within mammary stem cell-enriched fractions, suggesting that hedgehog exerts a mitogenic effect on mammary stem cells. Hedgehog signaling promotes differential TP63 promoter usage via disruption of Gli3 or Gli3R accumulation, and shRNA-mediated disruption of Gli3 expression was sufficient to alter TP63 promoter usage and enhance clonigenicity of mammary stem cells. Finally, hedgehog signaling is enhanced during pregnancy, where it contributes to expansion of the mammary progenitor compartment. These studies support a model in which hedgehog activates elaboration and differentiation of mammary progenitors via differential TP63 promoter selection and forfeiture of self-renewing capacity.

Original languageEnglish (US)
Pages (from-to)1253-1264
Number of pages12
JournalSTEM CELLS
Volume26
Issue number5
DOIs
StatePublished - May 1 2008
Externally publishedYes

Keywords

  • Gli3
  • Hedgehog
  • Mammary progenitors
  • Mammary stem cells
  • Quiescence
  • TP63

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

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