Handling editor: Patrick Tam
ABSTRACT
Ciliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies are characterized by craniofacial phenotypes such as craniosynostosis, cleft lip/palate and micrognathia. Patients with ciliopathic micrognathia experience a particular set of difficulties, including impaired feeding and breathing, and have extremely limited treatment options. To understand the cellular and molecular basis for ciliopathic micrognathia, we used the talpid2 (ta2), a bona fide avian model for the human ciliopathy oral-facial-digital syndrome subtype 14. Histological analyses revealed that the onset of ciliopathic micrognathia in ta2 embryos occurred at the earliest stages of mandibular development. Neural crest-derived skeletal progenitor cells were particularly sensitive to a ciliopathic insult, undergoing unchecked passage through the cell cycle and subsequent increased proliferation. Furthermore, whereas neural crest-derived skeletal differentiation was initiated, osteoblast maturation failed to progress to completion. Additional molecular analyses revealed that an imbalance in the ratio of bone deposition and resorption also contributed to ciliopathic micrognathia in ta2 embryos. Thus, our results suggest that ciliopathic micrognathia is a consequence of multiple aberrant cellular processes necessary for skeletal development, and provide potential avenues for future therapeutic treatments.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: S.A.B.; Methodology: C.L.B.P.; Validation: C.L.B.P., E.C.B.; Formal analysis: S.A.B.; Investigation: C.L.B.P., E.C.B., M.A.-P.; Resources: S.A.B.; Writing - original draft: C.L.B.P., S.A.B.; Writing - review & editing: C.L.B.P., E.C.B., S.A.B.; Visualization: C.L.B.P., E.C.B., S.A.B.; Supervision: S.A.B.; Project administration: S.A.B.; Funding acquisition: S.A.B.
Funding
This study was funded by the National Institute of Dental and Craniofacial Research (R35 DE027557) and Shriners Hospitals for Children (543938) to S.A.B. Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at https://dev.biologists.org/lookup/doi/10.1242/dev.194175.supplemental
- Received June 19, 2020.
- Accepted January 13, 2021.
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