Fgfr2iiib-mapk activity is required for epithelial cell fate decision in the lower müllerian duct

Jumpei Terakawa, Altea Rocchi, Vanida A. Serna, Erwin P. Bottinger, Jonathan M. Graff, Takeshi Kurita

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Abstract

Cell fate of lower Müllerian duct epithelium (MDE), to become uterine or vaginal epithelium, is determined by the absence or presence of hNp63 expression, respectively. Previously, we showed that SMAD4 and runt-related transcription factor 1 (RUNX1) were independently required for MDE to express ΔhNp63. Here, we report that vaginal mesenchyme directs vaginal epithelial cell fate in MDE through paracrine activation of fibroblast growth factor (FGF) receptor-MAPK pathway. In the developing reproductive tract, FGF7 and FGF10 were enriched in vaginal mesenchyme, whereas FGF receptor 2IIIb was expressed in epithelia of both the uterus and vagina. When Fgfr2 was inactivated, vaginal MDE underwent uterine cell fate, and this differentiation defect was corrected by activation of MEK-ERK pathway. In vitro, FGF10 in combination with bone morphogenetic protein 4 and activin A (ActA) was sufficient to induce hNp63 in MDE, and ActA was essential for induction of RUNX1 through SMAD-independent pathways. Accordingly, inhibition of type 1 receptors for activin in neonatal mice induced uterine differentiation in vaginal epithelium by down-regulating RUNX1, whereas conditional deletion of Smad2 and Smad3 had no effect on vaginal epithelial differentiation. In conclusion, vaginal epithelial cell fate in MDE is induced by FGF7/10-MAPK, bone morphogenetic protein 4-SMAD, and ActA-RUNX1 pathway activities, and the disruption in any one of these pathways results in conversion from vaginal to uterine epithelial cell fate.

Original languageEnglish (US)
Pages (from-to)783-795
Number of pages13
JournalMolecular Endocrinology
Volume30
Issue number7
DOIs
StatePublished - Jul 1 2016

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Epithelium
Epithelial Cells
Bone Morphogenetic Protein 4
Mesoderm
Core Binding Factor Alpha 2 Subunit
Type I Activin Receptors
Fibroblast Growth Factor Receptors
MAP Kinase Signaling System
Vagina
Uterus
Cell Differentiation
activin A

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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Fgfr2iiib-mapk activity is required for epithelial cell fate decision in the lower müllerian duct. / Terakawa, Jumpei; Rocchi, Altea; Serna, Vanida A.; Bottinger, Erwin P.; Graff, Jonathan M.; Kurita, Takeshi.

In: Molecular Endocrinology, Vol. 30, No. 7, 01.07.2016, p. 783-795.

Research output: Contribution to journalArticle

Terakawa, Jumpei ; Rocchi, Altea ; Serna, Vanida A. ; Bottinger, Erwin P. ; Graff, Jonathan M. ; Kurita, Takeshi. / Fgfr2iiib-mapk activity is required for epithelial cell fate decision in the lower müllerian duct. In: Molecular Endocrinology. 2016 ; Vol. 30, No. 7. pp. 783-795.
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