| Data source |
GEO: GSE151354
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| Description |
The specification and maintenance of distinct zones of chondrocytes within growth plates and joints ensures proper skeletal development through adulthood. Rare 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 joints in the distal limbs. Embryonic knockdown of nkx3.2 function in zebrafish had revealed a requirement in jaw joint specification, yet embryonic lethality of nkx3.2 knockdown zebrafish and mouse Nkx3.2 mutants had precluded an analysis of post-embryonic functions. Here we report adult viable nkx3.2 zebrafish mutants that display ectopic cartilage overgrowth in place of a missing jaw joint, as well as severe dysmorphologies of the facial skeleton, skullcap, and spine. We also isolate rare viable nkx3.2 knockdown animals that lack the jaw joint but fail to display ectopic cartilage growth and scoliosis, indicating post-embryonic roles for Nkx3.2 beyond jaw joint specification. Consistently, we observe nkx3.2 expression in the subarticular zone of the adult jaw joint and in pre-hypertrophic growth plate chondrocytes. Single-cell RNA sequencing reveals an upregulation of stress-induced pathways in mutants, including the prostaglandin D2 synthase ptgdsb.1 and the mTOR regulator sestrin1, which we confirm by in situ RNA analysis of the defective jaw joint region. Our data reveal a zebrafish model for the joint and spine defects of SMMD and point to post-embryonic roles for Nkx3.2 in buffering the stress response and dampening proliferation in joint-adjacent chondrocytes. |
| Key word |
nkx3.2; chondrocyte; proliferation; joint; spine; zebrafish;gene-expression; articular-cartil age; homeobox gene; danio-rerio; bmp signals; bapx1; growth; sox9; jaw |
| Publication |
Smeeton J, Natarajan N, Naveen Kumar A, Miyashita T et al. Zebrafish model for spondylo-megaepiphyseal-metaphyseal dysplasia reveals post-embryonic roles of Nkx3.2 in the skeleton. Development 2021 Jan 25;148(2). PMID: 33462117 |
| 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. |
