Defects of the spliceosomal gene SNRPB affect osteo‐ and chondro‐differentiation

Abstract

Although gene splicing occurs throughout the body, the phenotype of spliceosomal defects is largely limited to specific tissues. Cerebro‐costo‐mandibular syndrome (CCMS) is one such spliceosomal disease, which presents as congenital skeletal dysmorphism and is caused by mutations of SNRPB gene encoding Small Nuclear Ribonucleoprotein Polypeptides B/B′ (SmB/B′). This study employed in vitro cell cultures to monitor osteo‐ and chondro‐differentiation and examined the role of SmB/B′ in the differentiation process. We found that low levels of SmB/B′ by knockdown or mutations of SNRPB led to suppressed osteodifferentiation in Saos‐2 osteoprogenitor‐like cells, which was accompanied by affected splicing of Dlx5. On the other hand, low SmB/B′ led to promoted chondrogenesis in HEPM mesenchymal stem cells. Consistent with other reports, osteogenesis was promoted by the Wnt/β‐catenin pathway activator and suppressed by Wnt and BMP blockers, whereas chondrogenesis was promoted by Wnt inhibitors. Suppressed osteogenic markers by SNRPB knockdown were partly rescued by Wnt/β‐catenin pathway activation. Reporter analysis revealed that suppression of SNRPB results in attenuated Wnt pathway and/or enhanced BMP pathway activities. SNRPB knockdown altered splicing of TCF7L2 which impacts Wnt/β‐catenin pathway activities. This work helps unravel the mechanism underlying CCMS whereby reduced expression of spliceosomal proteins causes skeletal phenotypes.