Regulation of terminal hypertrophic chondrocyte differentiation in Prmt5 mutant mice modeling infantile idiopathic scoliosis

Dis Model Mech. 2019 Dec 17;12(12):dmm041251. doi: 10.1242/dmm.041251.

Abstract

Idiopathic scoliosis (IS) is the most common type of musculoskeletal defect affecting children worldwide, and is classified by age of onset, location and degree of spine curvature. Although rare, IS with onset during infancy is the more severe and rapidly progressive form of the disease, associated with increased mortality due to significant respiratory compromise. The pathophysiology of IS, in particular for infantile IS, remains elusive. Here, we demonstrate the role of PRMT5 in the infantile IS phenotype in mouse. Conditional genetic ablation of PRMT5 in osteochondral progenitors results in impaired terminal hypertrophic chondrocyte differentiation and asymmetric defects of endochondral bone formation in the perinatal spine. Analysis of these several markers of endochondral ossification revealed increased type X collagen (COLX) and Ihh expression, coupled with a dramatic reduction in Mmp13 and RUNX2 expression, in the vertebral growth plate and in regions of the intervertebral disc in the Prmt5 conditional mutant mice. We also demonstrate that PRMT5 has a continuous role in the intervertebral disc and vertebral growth plate in adult mice. Altogether, our results establish PRMT5 as a critical promoter of terminal hypertrophic chondrocyte differentiation and endochondral bone formation during spine development and homeostasis.This article has an associated First Person interview with the first author of the paper.

Keywords: Chondrocyte terminal differentiation; Endochondral ossification; Infantile scoliosis; PRMT5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Bone Morphogenetic Protein 4 / genetics*
  • Bone Morphogenetic Protein 4 / metabolism
  • Cartilage / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Chondrocytes / cytology*
  • Chondrogenesis
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Crosses, Genetic
  • Gene Deletion
  • Gene Expression Regulation, Developmental*
  • Hedgehog Proteins / metabolism
  • Homeostasis
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • Mutation
  • Osteogenesis / genetics
  • Phenotype
  • Promoter Regions, Genetic
  • Protein-Arginine N-Methyltransferases / genetics*
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Scoliosis / genetics*
  • Stem Cells / cytology

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Core Binding Factor Alpha 1 Subunit
  • Hedgehog Proteins
  • Runx2 protein, mouse
  • ihh protein, mouse
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse