# Function and Regulation of Sema3 Genes in Palate Development and Innervation

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $238,500

## Abstract

Abstract
 Cleft palate is a common birth defect in humans and causes significant problems in feeding, speech, and
increased mortality. While most cleft palate patients receive surgical repair to restore an anatomically intact
palate, about 30% of children with a repaired palate still experience significant functional palate deficit and/or
velopharyngeal dysfunction (VPD), which impairs speech and significantly affects quality of life. Orofacial
malformations, including cleft or high-arched palate and flattened nasal bridge, and nasal dysarthria are major
features of congenital facial palsy conditions such as the Moebius syndrome (OMIM 157900), suggesting that
facial/palatal innervation is intimately linked to palate morphogenesis and velopharyngeal function. However,
nothing is currently known about the molecular mechanisms regulating palate innervation and their integration
with the overall mechanisms regulating palate morphogenesis. We have discovered that mice lacking the zinc
finger transcription factor Osr2 exhibit complete cleft palate and dramatic disruption of palatal innervation. We
previously demonstrated that Osr2 is a key intrinsic regulator of palatal shelf growth and integrates the
functions of several major molecular pathways, including SHH signaling and the transcription factor Pax9-
mediated regulation of palate morphogenesis. Through RNA-seq transcriptome profiling we found that
expression of three physically linked members of the Sema3 gene family, Sema3a, Sema3d, and Sema3e,
was significantly upregulated in the developing palatal mesenchyme in Osr2 mutant embryos. The Sema3
proteins were originally identified as negative mediators of axonal guidance in the central nervous system
and have since been shown to play crucial roles in many other developmental processes, including neural
crest migration, endothelial migration and vasculogenesis, and osteoblast differentiation. Our central
hypothesis is that proper regulation of expression of the Sema3 genes during palate development is crucial
for not only palate innervation but also palate morphogenesis. Recently mutations in PLXND1, which encodes
a receptor for SEMA3 proteins, and a complex chromosomal rearrangement disrupting both the SEMA3A and
SEMA3D genes, have been associated with Moebius syndrome, suggesting that the SEMA3-PLXND1
pathway plays crucial roles in cranial nerve development and palate morphogenesis in humans as well. To
better understand the function and regulation of the Sema3 genes in palate development and innervation, we
will use a combination of multi-omics approaches, CRISPR/Cas9-mediated genome editing, and compound
mutant mouse studies to unravel the molecular network involving Osr2 and the Sema3 genes in the regulation
of palate innervation and morphogenesis. Data from these studies will fill a long standing major gap in the
understanding of pathogenic mechanisms of cleft palate and VPD, which will help to significantly improve
strategies for diagnosis, c...

## Key facts

- **NIH application ID:** 10105940
- **Project number:** 1R21DE030193-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Yu Lan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $238,500
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105940

## Citation

> US National Institutes of Health, RePORTER application 10105940, Function and Regulation of Sema3 Genes in Palate Development and Innervation (1R21DE030193-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10105940. Licensed CC0.

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