Centriolar Protein C2cd3 Is Required for Craniofacial Development

Chang, Che Shoa; Brown, Kari; Yang, Yanfen; Brugmann, Samantha A.

doi:10.3389/fcell.2021.647391

Cited by 4 publications

(2 citation statements)

References 48 publications

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“…Third, the AP2-Cre driver recombined in the surface and oral ectoderm, the CNCC-derived mesenchyme, and the neuroectoderm (Macatee et al, 2003). To determine the tissue-specific requirement for C2cd3 function, we utilized previously generated mice with a C2cd3 ex4-5flox allele (Chang et al, 2021) in combination with these Cre drivers (Fig. 4A-D) and assayed the resulting Meckel’s cartilage phenotype.…”

Section: Resultsmentioning

confidence: 99%

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The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

Brooks,

Han,

Bonatto Paese

et al. 2024

Preprint

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The mandible is composed of several musculoskeletal tissues including bone, cartilage, and tendon that require precise patterning to ensure structural and functional integrity. Interestingly, most of these tissues are derived from one multipotent cell population called cranial neural crest cells (CNCCs). How CNCCs are properly instructed to differentiate into various tissue types remains nebulous. To better understand the mechanisms necessary for the patterning of mandibular musculoskeletal tissues we utilized the avian mutanttalpid2(ta2) which presents with several malformations of the facial skeleton including dysplastic tendons, mispatterned musculature, and bilateral ectopic cartilaginous processes extending off Meckel’s cartilage. We found an ectopic epithelial BMP signaling domain in theta2mandibular prominence (MNP) that correlated with the subsequent expansion ofSOX9+ cartilage precursors. These findings were validated with conditional murine models suggesting an evolutionarily conserved mechanism for CNCC-derived musculoskeletal patterning. Collectively, these data support a model in which cilia are required to define epithelial signal centers essential for proper musculoskeletal patterning of CNCC-derived mesenchyme.

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Section: Resultsmentioning

confidence: 99%

“…All mouse strains used in this study have been previously described: AP2-Cre (Macatee et al, 2003), C2cd3 ex4-5flox (Chang et al, 2021), Crect (Reid et al, 2011), Scx-Cre (Blitz et al, 2009), and Wnt1-Cre2 (Lewis et al, 2013). Both male and female mice were used.…”

Section: Methodsmentioning

confidence: 99%

The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

Brooks,

Han,

Bonatto Paese

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

Brooks,

Han,

Bonatto Paese

et al. 2024

Differentiation

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Use of patient-derived cell models for characterization of compound heterozygous hypomorphic C2CD3 variants in a patient with isolated nephronophthisis

Sentell,

Mougharbel,

Nurcombe

et al. 2024

Human Molecular Genetics

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Background Primary ciliopathies are a heterogeneous group of rare disorders predominantly caused by autosomal-recessive genetic variants that disrupt non-motile ciliary function. They often manifest as a syndromic phenotype, frequently involving the kidney. Biallelic pathogenic variants in C2CD3 disrupt ciliogenesis and Sonic Hedgehog (SHH) signaling, resulting in a severe ciliopathy (Orofaciodigital syndrome XIV, OMIM 615948). We present compound heterozygous missense variants in C2CD3 that partially disrupt ciliary function in a patient with isolated renal disease. Methods Exome sequencing identified biallelic C2CD3 missense variants (p.Pro168Leu; p.Thr2079Met). Patient-derived fibroblasts and urinary renal epithelial cells (URECs), and human RPE-1 C2CD3 knockout (KO) cell-lines were used for in vitro studies. Results Cilia length was significantly shorter in patient-derived fibroblasts compared to an unaffected sibling (2.309 vs. 2.850 μm, P < 0.0001), while URECs showed significantly shortened cilia (2.068 vs. 2.807 μm, P < 0.0001) and a 40.8% reduction in ciliation (P < 0.001). The latter was not observed in fibroblasts, suggesting a kidney-specific effect. SHH signaling was dysregulated in patient cells as expression of GLI3 activator protein and GLI1 mRNA was significantly reduced. C2CD3 localization to the basal body was significantly reduced in patient URECs. Finally, rescue experiments in C2CD3 KO RPE-1 cells corroborated these findings by demonstrating a reduced capacity to restore ciliogenesis for each variant. Conclusion Biallelic hypomorphic missense variants in C2CD3 may contribute to an isolated nephronophthisis phenotype with impaired ciliogenesis and SHH signaling. Our findings underscore the importance of functional testing to characterize candidate gene-disease relationships in patients with nephropathy of unknown etiology.

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Centriolar Protein C2cd3 Is Required for Craniofacial Development

Cited by 4 publications

References 48 publications

The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

The ciliary protein C2cd3 is required for mandibular musculoskeletal tissue patterning

Use of patient-derived cell models for characterization of compound heterozygous hypomorphic C2CD3 variants in a patient with isolated nephronophthisis

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