FGF9 Promotes Expression of HAS2 in Palatal Elevation via the Wnt/β-Catenin/TCF7L2 Pathway

Yidan Sun; Xiyu Ying; Ruomei Li; Mengjia Weng; Jiajun Shi; Zhenqi Chen

doi:10.3390/biom12111639

FGF9 Promotes Expression of HAS2 in Palatal Elevation via the Wnt/β-Catenin/TCF7L2 Pathway

Biomolecules. 2022 Nov 4;12(11):1639. doi: 10.3390/biom12111639.

Authors

Yidan Sun¹, Xiyu Ying¹, Ruomei Li¹, Mengjia Weng², Jiajun Shi¹, Zhenqi Chen¹

Affiliations

¹ Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai 200011, China.
² Department of Stomatology, Huadong Hospital, Fudan University, Shanghai 200040, China.

Abstract

Background: Fgf9 mutation was found in cleft palate patients. Our previous study indicated that Fgf9 promotes timely elevation of palate by regulating hyaluronic acid (HA) accumulation at embryonic day 13.5 (E13.5). HA is synthesized by hyaluronic acid synthases (HAS) isoforms 1, 2, or 3. However, how FGF9 regulates HA in palatogenesis is still unclear.

Methods: Using Ddx4-Cre mice, we generated the Fgf9^-^/^- mouse model (with exon 2 deletion). Immunohistochemistry was used to detect the location and expression of HAS2 in WT and the Fgf9^-^/^- palate at E13.5. We also predicted the association between Fgf9 and Has2 within the developing palate by performing a bioinformatics analysis. The expression of β-catenin, HAS2, and TCF7L2 were verified by Western blotting after knockout of Fgf9. Rescue experiments were performed by ELISA in vitro.

Results: Fgf9^-^/^- mice exhibited 100% penetrance of the cleft palate. A knockout of Fgf9 confirmed that HAS2 and TCF7L2 expression was positively correlated with FGF9. TCF7L2 binds to the Has2 promoter, exhibiting the high specificity predicted by JASPAR. Additionally, increased HA expression by BML-284, TCF-dependent agonist, was blocked in Fgf9^-^/^- palate because of the significant decline in TCF7L2 expression.

Conclusions: FGF9 promotes HAS2 expression via Wnt/β-catenin/TCF7L2 pathway with TCF7L2 activating transcription of Has2 in the palate.

Keywords: FGF9; HAS2; TCF7L2; Wnt/β-catenin pathway; hyaluronic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cleft Palate* / genetics
Fibroblast Growth Factor 9 / genetics
Hyaluronic Acid
Mice
Transcription Factor 7-Like 2 Protein / genetics
Wnt Signaling Pathway
beta Catenin*

Substances

beta Catenin
Hyaluronic Acid
Fgf9 protein, mouse
Fibroblast Growth Factor 9
Tcf7l2 protein, mouse
Transcription Factor 7-Like 2 Protein

Grants and funding

This research was funded by Clinical Research Program of Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, grant number No. JYLJ202004.