Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage-Hair Hypoplasia via Enhanced Wnt/β-Catenin Signaling

Abstract

Cartilage‐hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by bone dysplasia and many other highly variable features. The gene responsible for CHH is 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; in addition, there are no viable animal models for CHH. We generated an rmrp KO 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. We also demonstrate that rmrp mutation upregulates canonical Wnt/β‐catenin signaling; the 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, hence deepening our understanding of the role of rmrp in skeleton development.

RNA polymerase III transcription as a disease factor

“…Targeting a conserved region of rmrp in zebrafish and reducing its level led to some CHH phenotypes, as well as to decreased cell proliferation, increased apoptosis, and increased lethality 12-14 d after fertilization. The effect of rmrp deficiency was attributed to increased Wnt/β-catenin signaling, as inhibition of Wnt/β-catenin partially alleviated the phenotype of rmrp deficit (Sun et al 2019).…”

Ribosomopathies: New Therapeutic Perspectives

“…RMRP mutations have been associated with inhibition of intramembranous ossification of skull bones and activation of vertebrae ossification. Moreover, disrupted RMRP inhibits cell proliferation, promotes apoptosis and activates the Wnt/β-catenin pathway, probably by suppressing the degradation of β-catenin [ 92 ].…”

Zebrafish: A Resourceful Vertebrate Model to Investigate Skeletal Disorders

“…The Tg (sp7:EGFP) b 1212 line allowed osteoblast behavior to be studied during both intramembranous and endochondral ossification. Moreover, this line was used to investigate the abnormal perichondral ossification in the RNA component of the mitochondrial RNA-processing endoribonuclease ( rmrp ) knock-out zebrafish model of cartilage hair hypoplasia ( 65 ). Tg(Ola.sp7 : mCherry) zf 131 was crossed with the OI type XIII zebrafish model frilly fins to elucidate the role of the bone morphogenic protein 1, encoded by bmp1a gene, in osteoblast differentiation and localization ( 94 ).…”