PRMT1-SFPQ regulates intron splicing to control matrix gene expression during craniofacial development

ABSTRACT: Spliceosomopathies, which are a group of disorders caused by defects in the splicing machinery, frequently affect the craniofacial skeleton. However, the cell-autonomous roles of the splicing machinery in craniofacial development remain incompletely understood. In exploring the splicing mechanisms in CNCCs, we have focused on protein arginine methyltransferases which catalyze the arginine methylation of splicing factors to modify splicing factor expression and activity, influencing the splicing product. PRMT1 is the highest expressing enzyme of the arginine methyltransferase family in cranial neural crest cells (CNCCs) and its role in craniofacial development is evident based on our earlier investigation, where CNCC-specific Prmt1 deletion caused cleft palate and mandibular hypoplasia. In the present study, we revealed previously unrecognized functions of PRMT1 in CNCCs in the regulation of intron retention, a type of alternative splicing where introns are retained in the mature mRNA sequence. Mandibular primordium of Prmt1-deficient embryos demonstrated an increase in percentage of intron-retaining mRNA of matrix genes, which triggered NMD-mediated mRNA degradation, causing a reduction in matrix transcript expression. We further identified SFPQ as a catalytic substrate of PRMT1 in the developing craniofacial structures, that depend on PRMT1 for arginine methylation and protein expression. Depletion of SFPQ in CNCCs phenocopied PRMT1 deletion in that matrix transcripts contained higher IR and exhibited lower expression and additionally demonstrated alteration in Wnt signaling components and neuronal genes. We further recognized an impairment of long intron and long gene splicing as a common feature among SFPQ-regulated genes in CNCCs, in which SFPQ depletion elevated retention of long introns or introns in long genes of matrix, Wnt signaling, and neuronal pathways. Together, these findings uncovered the PRMT1-SFPQ pathway that modulates matrix expression via control of intron splicing in CNCCs during craniofacial development.

ORGANISM(S): Mus musculus

PROVIDER: GSE266474 | GEO | 2026/09/11

REPOSITORIES: GEO