Handling Editor: Steve Wilson
ABSTRACT
The regulated expansion of chondrocytes within growth plates and joints ensures proper skeletal development through adulthood. Mutations in the transcription factor NKX3.2 underlie spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD), which is characterized by skeletal defects including scoliosis, large epiphyses, wide growth plates and supernumerary distal limb joints. Whereas nkx3.2 knockdown zebrafish and mouse Nkx3.2 mutants display embryonic lethal jaw joint fusions and skeletal reductions, respectively, they lack the skeletal overgrowth seen in SMMD patients. Here, we report adult viable nkx3.2 mutant zebrafish displaying cartilage overgrowth in place of a missing jaw joint, as well as severe dysmorphologies of the facial skeleton, skullcap and spine. In contrast, cartilage overgrowth and scoliosis are absent in rare viable nkx3.2 knockdown animals that lack jaw joints, supporting post-embryonic roles for Nkx3.2. Single-cell RNA-sequencing and in vivo validation reveal increased proliferation and upregulation of stress-induced pathways, including prostaglandin synthases, in mutant chondrocytes. By generating a zebrafish model for the skeletal overgrowth defects of SMMD, we reveal post-embryonic roles for Nkx3.2 in dampening proliferation and buffering the stress response in joint-associated chondrocytes.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author Contributions
Conceptualization: J.S., J.G.C.; Methodology: J.S., N.N., T.M., P.B.; Software: J.S., P.F.; Validation: J.S., N.N., A.N.K., P.F.; Formal analysis: J.S., N.N., A.N.K., T.M., P.B., D.G., J.G.C.; Investigation: J.S., N.N., A.N.K., T.M., P.B., P.F.; Resources: P.F., D.G., J.G.C.; Data curation: J.S., P.F.; Writing - original draft: J.S., J.G.C.; Writing - review & editing: J.S., P.F., J.G.C.; Visualization: J.S., P.B.; Supervision: D.G., J.G.C.; Project administration: J.G.C.; Funding acquisition: J.S., D.G., J.G.C.
Funding
This work was supported by National Institutes of Health grants R00DE027218 (to J.S.) and R35DE027550 (to J.G.C), and Natural Sciences and Engineering Research Council of Canada grant RGPIN-2014-06311 (to D.G.). Deposited in PMC for release after 12 months.
Data availability
RNA-seq files have been deposited in GEO under accession number GSE151354.
Supplementary information
Supplementary information available online at https://dev.biologists.org/lookup/doi/10.1242/dev.193409.supplemental
- Received June 1, 2020.
- Accepted December 31, 2020.
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