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RESEARCH ARTICLE
Zebrafish model for spondylo-megaepiphyseal-metaphyseal dysplasia reveals post-embryonic roles of Nkx3.2 in the skeleton
Joanna Smeeton, Natasha Natarajan, Arati Naveen Kumar, Tetsuto Miyashita, Pranidhi Baddam, Peter Fabian, Daniel Graf , J. Gage Crump
Development 2021 148: dev193409 doi: 10.1242/dev.193409 Published 25 January 2021
Joanna Smeeton
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
2Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, and Department of Genetics and Development, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
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  • For correspondence: gcrump@usc.edu jms2504@cumc.columbia.edu
Natasha Natarajan
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Arati Naveen Kumar
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Tetsuto Miyashita
3Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada
4Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, USA
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Pranidhi Baddam
5Department of Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
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Peter Fabian
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Daniel Graf 
5Department of Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
6Department of Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2R7, Canada
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J. Gage Crump
1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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  • For correspondence: gcrump@usc.edu jms2504@cumc.columbia.edu

Handling Editor: Steve Wilson

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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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Keywords

  • Nkx3.2
  • Chondrocyte
  • Proliferation
  • Joint
  • Spine
  • Zebrafish

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RESEARCH ARTICLE
Zebrafish model for spondylo-megaepiphyseal-metaphyseal dysplasia reveals post-embryonic roles of Nkx3.2 in the skeleton
Joanna Smeeton, Natasha Natarajan, Arati Naveen Kumar, Tetsuto Miyashita, Pranidhi Baddam, Peter Fabian, Daniel Graf , J. Gage Crump
Development 2021 148: dev193409 doi: 10.1242/dev.193409 Published 25 January 2021
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RESEARCH ARTICLE
Zebrafish model for spondylo-megaepiphyseal-metaphyseal dysplasia reveals post-embryonic roles of Nkx3.2 in the skeleton
Joanna Smeeton, Natasha Natarajan, Arati Naveen Kumar, Tetsuto Miyashita, Pranidhi Baddam, Peter Fabian, Daniel Graf , J. Gage Crump
Development 2021 148: dev193409 doi: 10.1242/dev.193409 Published 25 January 2021

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