PUBLICATION
Zebrafish Model for Spondylo-Megaepiphyseal-Metaphyseal Dysplasia Reveals Post-Embryonic Roles of Nkx3.2 in the Skeleton
- Authors
- Smeeton, J., Natarajan, N., Naveen Kumar, A., Miyashita, T., Baddam, P., Fabian, P., Graf, D., Crump, J.G.
- ID
- ZDB-PUB-210120-15
- Date
- 2021
- Source
- Development (Cambridge, England) 148(2): (Journal)
- Registered Authors
- Crump, Gage DeKoeyer
- Keywords
- Chondrocyte, Joint, Nkx3.2, Proliferation, Spine, Zebrafish
- Datasets
- GEO:GSE151354
- MeSH Terms
-
- Animals
- Bone and Bones/embryology*
- Bone and Bones/metabolism*
- Cartilage/embryology
- Cartilage/pathology
- Chondrocytes/metabolism
- Disease Models, Animal
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/pathology
- Gene Expression Regulation, Developmental
- Homeodomain Proteins/metabolism*
- Jaw/embryology
- Jaw/pathology
- Joints/abnormalities
- Joints/embryology
- Joints/pathology
- Mitosis/genetics
- Morpholinos/pharmacology
- Mutation/genetics
- Osteochondrodysplasias/embryology*
- RNA-Seq
- Single-Cell Analysis
- Skull/abnormalities
- Skull/embryology
- Skull/pathology
- Spine/abnormalities
- Spine/embryology
- Spine/pathology
- Stress, Physiological/genetics
- Transcription Factors/metabolism*
- Up-Regulation/genetics
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 33462117 Full text @ Development
Citation
Smeeton, J., Natarajan, N., Naveen Kumar, A., Miyashita, T., Baddam, P., Fabian, P., Graf, D., Crump, J.G. (2021) Zebrafish Model for Spondylo-Megaepiphyseal-Metaphyseal Dysplasia Reveals Post-Embryonic Roles of Nkx3.2 in the Skeleton. Development (Cambridge, England). 148(2):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping