# Cellular and molecular mechanisms of orofacial clefts

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $655,098

## Abstract

PROJECT SUMMARY/ABSTRACT
Orofacial clefts are one of the most common birth defects, affecting about 220,000 newborns each year. The
cause and prevention of orofacial clefts remain poorly understood. We have uncovered that the Lrp6-mediated
Wnt/ß-catenin signaling pathway is required for lip and palate formation and fusion, which may act through
positive regulation of the Msx homeobox-containing genes, and may repress a retinoic acid-synthesizing
enzyme in the orofacial primordia. Orofacial development involves both orofacial mesenchymal expansion and
ectodermal/epithelial fusion processes. We demonstrated that either loss- or gain-of-function of facial
ectodermal ß-catenin signaling arrested the formation and patterning of orofacial primordia, which may act
through transcriptional regulation of Fgf8, a critical signaling molecule in the facial ectoderm and anterior
neural ridge (a regional signaling center). Loss- or gain-of-function of palatal epithelial ß-catenin caused cleft
palate. These studies suggest that Wnt/ß-catenin signaling activity is tightly regulated during normal orofacial
morphogenesis and that either hypo- or hyperactivity of Wnt/ß-catenin signaling may cause orofacial birth
defects. However, the regulatory mechanism of Wnt/ß-catenin signaling pathway during orofacial development
remains almost unknown and will be addressed in this study. Orofacial clefts can be caused by gene mutations
and/or environmental factors. The latter may affect epigenetic processes, such as DNA methylation and
chromatin modification, to regulate gene expression activities without altering the genomic sequence.
Nevertheless, epigenetic mechanisms of orofacial clefts remain poorly understood. We hypothesize that
epigenetic factors regulate appropriate Wnt/ß-catenin signaling activities for lip/palate formation and fusion.
Specific Aim 1 will address the role of two epigenetic regulators that may lead to orofacial clefts if they are not
properly regulated. Specific Aim 2 will test genetic interactions and/or the genetic rescue of key Wnt/ß-catenin
signaling components and the epigenetic factors in orofacial clefts. Specific Aim 3 will test the hypothesis that
epigenetic modulation of Wnt/ß-catenin signaling can prevent orofacial clefts in mutant animal models.
Successful completion of the proposed research will provide new insights into the genetic and epigenetic
mechanisms of orofacial clefts, which may translate into clinical applications to treat orofacial birth defects
through manipulation of key regulatory processes.

## Key facts

- **NIH application ID:** 9954043
- **Project number:** 5R01DE026737-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Chengji Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $655,098
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954043

## Citation

> US National Institutes of Health, RePORTER application 9954043, Cellular and molecular mechanisms of orofacial clefts (5R01DE026737-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9954043. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*