Rmrp mutation disrupts chondrogenesis and bone ossification in zebrafish model of cartilage-hair hypoplasia via enhanced Wnt/β-catenin signaling

Sun, X., Zhang, R., Liu, M., Chen, H., Chen, L., Luo, F., Zhang, D., Huang, J., Li, F., Ni, Z., Qi, H., Su, N., Jin, M., Yang, J., Tan, Q., Du, X., Chen, B., Huang, H., Chen, S., Yin, L., Xu, X., Deng, C., Luo, L., Xie, Y., Chen, L.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research   34(11): 2101-2116 (Journal)
Registered Authors
Chen, Lin, Luo, Lingfei
Cartilage-hair hypoplasia, RMRP, Skeletal development, Wnt/β-catenin, Zebrafish
MeSH Terms
  • Animals
  • Chondrogenesis/genetics*
  • Disease Models, Animal
  • Hair/abnormalities*
  • Hair/metabolism
  • Hair/pathology
  • Hirschsprung Disease*/genetics
  • Hirschsprung Disease*/metabolism
  • Hirschsprung Disease*/pathology
  • Humans
  • Mutation*
  • Osteochondrodysplasias/congenital*
  • Osteochondrodysplasias/genetics
  • Osteochondrodysplasias/metabolism
  • Osteochondrodysplasias/pathology
  • Osteogenesis/genetics*
  • Primary Immunodeficiency Diseases*/genetics
  • Primary Immunodeficiency Diseases*/metabolism
  • Primary Immunodeficiency Diseases*/pathology
  • RNA, Long Noncoding*/genetics
  • RNA, Long Noncoding*/metabolism
  • Skull/metabolism
  • Skull/pathology
  • Spine/metabolism
  • Spine/pathology
  • Wnt Signaling Pathway/genetics*
  • Zebrafish/metabolism*
31237961 Full text @ J. Bone Miner. Res.
Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by bone dysplasia and many other highly variable features. The responsible gene for CHH has been identified to be the RNA component of the mitochondrial RNA processing endoribonuclease (RMRP) gene. Currently, the pathogenesis of osteochondrodysplasia and extraskeletal manifestations in CHH patients remains incompletely understood, furthermore, there are no viable animal models for CHH. We generated a rmrp knockout zebrafish model to study the developmental mechanisms of CHH. We found that rmrp is required for the patterning and shaping of pharyngeal arches. Rmrp mutation inhibits the intramembranous ossification of skull bones and promotes vertebrae ossification. The abnormalities of endochondral bone ossification are variable depending on the degree of dysregulated chondrogenesis. Moreover, rmrp mutation inhibits cell proliferation and promotes apoptosis through dysregulating the expressions of cell cycle and apoptosis related genes. Furthermore, we demonstrate that rmrp mutation up-regulates canonical Wnt/β-catenin signaling and pharmacological inhibition of Wnt/β-catenin could partially alleviate the chondrodysplasia and increased vertebrae mineralization in rmrp mutants. Our study, by establishing a novel zebrafish model for CHH, partially reveals the underlying mechanism of CHH, which also deepen our understanding of the role of rmrp in skeleton development. This article is protected by copyright. All rights reserved.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes