Folate Regulation of Planar Cell Polarity Pathway and F-Actin Through Folate Receptor Alpha

Authors

Xiao Han
Xuanye Cao
Robert M Cabrera
Paula Andrea Pimienta Ramirez
Ying Linda Lin
Bogdan J Wlodarczyk
Cuilian Zhang
Richard H Finnell
Yunping Lei

Publication Date

1-1-2024

Journal

The FASEB Journal

DOI

10.1096/fj.202300202R

PMID

38095297

PMCID

PMC10754249

PubMedCentral® Posted Date

1-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Mice, Folic Acid, Actins, Folate Receptor 1, Cell Polarity, Fibroblasts, Wnt Signaling Pathway, Neural Tube Defects, Folic Acid Deficiency, Folic acid, 5-methyltetrahydrofolate, FOLR1, Vangl2, PCP signaling pathway, F-actin

Abstract

Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, Folic acid (FA) and 5-methyltetrahydrofolate(5mTHF), at concentration of 5uM, 500nM, 50nM and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages and cell proliferation and F-actin was monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and F-actin formation. We also found that FOLR1 protein level was positively regulated by folate concentration and the non-canonical Wnt/planar cell polarity (PCP) pathway signaling was significantly enriched among different folate conditions in RNA sequencing analyses. We demonstrated for the first time that FOLR1 could promote the transcription of Vangl2, one of PCP core genes. The transcription of Vangl2 was down regulated under folate-deficient condition, which resulted in a decrease of PCP activity and F-actin formation. In summary, we identified a distinct advantage of FA in cell proliferation and F-actin formation over 5mTHF, as well as demonstrating that FOLR1 could promote transcription of Vangl2 and provide a new mechanism by which folate deficiency can contribute to the etiology of NTDs.

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