# Role of the Ciliary Protein C2CD3 in Mandibular Skelotogenesis

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $40,584

## Abstract

Project Summary/Abstract
Primary cilia are non-motile, microtubule-based organelles that protrude from the cellular membrane to sense
the cell’s external environment and to coordinate the transduction of multiple signaling pathways. Disruptions in
the structure or function of primary cilia result in a class of disorders known as ciliopathies. The skeleton is often
affected in ciliopathies as ciliopathy patients often present with osteochondrodysplasias (OCDPs) - anomalies of
bone and cartilage - such as micrognathia and mandibular dysmorphology. Oral-facial-digital syndromes are a
subset of ciliopathies that present with several OCDPs. There is considerable phenotypic overlap between
subtypes of oral-facial-digital syndromes and among other skeletal ciliopathies, making them difficult to properly
diagnose and differentiate from each other. The substantial degree of phenotypic overlap of ciliopathies that
affect the skeleton combined with the lack of a cure for ciliopathic OCDPs make this an issue of significant
biomedical concern. This proposed work focuses on understanding the requirement of the ciliary protein C2cd3
during the development of the mandibular skeleton by utilizing the avian C2CD3 mutant talpid2 (ta2) and the
conditional C2cd3fl/fl mouse. C2cd3 localizes to the distal centrioles of primary cilia and is required for
ciliogenesis. Mutations in C2cd3 result in the human ciliopathy Oral-facial-digital syndrome subtype 14. My
preliminary data indicates that talpid2 embryos present with numerous mandibular OCDPs, such as bilateral
Meckel’s chondrodysplasias and hypoplastic skeletal elements. There has yet to be an in-depth study as to how
these phenotypes arise. In Aim 1, I will determine if the bilateral Meckel’s chondrodysplasias are exostoses -
cartilage-capped bony tumors defined by lack of cellular polarity and ciliary extension, reduced Ext1/2
expression, and reduced heparan sulfate synthesis. ta2 embryos also possess increased FGF8 expression in
the developing mandible, but it is not known if this leads to mandibular bone hypoplasia. For Aim 2, I will
determine if expanded mandibular FGF8 signaling is sufficient to induce ta2 mandibular skeletal hypoplasia using
bead implantations in the developing avian mandible. Lastly, C2cd3 is expressed ubiquitously throughout the
developing embryo and it is not known if loss of C2cd3 in the craniofacial epithelium or mesenchyme leads to
mandibular OCDP. For Aim 3, I will breed C2cd3fl/fl mice with the dHAND-Cre and Crect mice to conditionally
delete C2cd3 in the mandibular mesenchyme and epithelium to determine if C2cd3 loss in either tissue type
results in mandibular OCDP. This study is important for advancing our understanding of the cellular and
molecular etiology of mandibular OCDPs in ciliopathic patients. A greater understanding of the developmental
mechanisms of mandibular OCDPs in ciliopathies is necessary for further refined diagnosis and the development
of less invasive therapeutic ...

## Key facts

- **NIH application ID:** 10368944
- **Project number:** 5F31DE030664-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Evan Cortez Brooks
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $40,584
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368944

## Citation

> US National Institutes of Health, RePORTER application 10368944, Role of the Ciliary Protein C2CD3 in Mandibular Skelotogenesis (5F31DE030664-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10368944. Licensed CC0.

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