Fibroblast Growth Factor 9 (FGF9)-pituitary Homeobox 2 (PITX2) Pathway Mediates Transforming Growth Factor β (TGFβ) Signaling to Regulate Cell Proliferation in Palatal Mesenchyme During Mouse Palatogenesis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Nov 30

PMID 22123828

Citations 42

Authors

Jun-Ichi Iwata

Lily Tung

Mark Urata

Joseph G Hacia

Richard Pelikan

Akiko Suzuki

Liza Ramenzoni

Obaid Chaudhry

Carolina Parada

Pedro A Sanchez-Lara

Yang Chai

Affiliations

Soon will be listed here.

Abstract

Cleft palate represents one of the most common congenital birth defects. Transforming growth factor β (TGFβ) signaling plays crucial functions in regulating craniofacial development, and loss of TGFβ receptor type II in cranial neural crest cells leads to craniofacial malformations, including cleft palate in mice (Tgfbr2(fl/fl);Wnt1-Cre mice). Here we have identified candidate target genes of TGFβ signaling during palatal formation. These target genes were selected based on combining results from gene expression profiles of embryonic day 14.5 palates from Tgfbr2(fl/fl);Wnt1-Cre mice and previously identified cleft palate phenotypes in genetically engineered mouse models. We found that fibroblast growth factor 9 (Fgf9) and transcription factor pituitary homeobox 2 (Pitx2) expressions are significantly down-regulated in the palate of Tgfbr2(fl/fl);Wnt1-Cre mice, and Fgf9 and Pitx2 loss of function mutations result in cleft palate in mice. Pitx2 expression is down-regulated by siRNA knockdown of Fgf9, suggesting that Fgf9 is upstream of Pitx2. We detected decreased expression of both cyclins D1 and D3 in the palates of Tgfbr2(fl/fl);Wnt1-Cre mice, consistent with the defect in cell proliferation. Significantly, exogenous FGF9 restores expression of cyclins D1 and D3 in a Pitx2-dependent manner and rescues the cell proliferation defect in the palatal mesenchyme of Tgfbr2(fl/fl);Wnt1-Cre mice. Our study indicates that a TGFβ-FGF9-PITX2 signaling cascade regulates cranial neural crest cell proliferation during palate formation.

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