Ph.D. Candidate McGill University Montreal, Quebec, Canada
Abstract Body : Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for Cerebro-costo-mandibular Syndrome (CCMS). CCMS is a rare congenital disorder commonly characterized by microcephaly, micrognathia, cleft palate, and varying degrees of rib abnormalities. Previously, we found that Snrpb heterozygous mouse embryos arrest shortly after implantation. Although heterozygous deletion of Snrpb in the developing brain and neural crest cells modeled craniofacial malformations found in CCMS patients, a model with high clinical relevance that can capture the full spectrum of CCMS symptoms is still lacking. Using the tamoxifen (TAM) inducible Cre recombinase system, we induced heterozygous deletion of Snrpb via tamoxifen injection during mid-gestation. We then characterized the phenotypes of mutant embryos with tamoxifen-induced Snrpb deletion across different developmental stages. Notably, we identified distinct rib and vertebral anomalies, including posterior rib gaps, a bell-shaped thorax, and scoliosis—characteristic hallmarks of CCMS in E17.5 mutant embryos. With this CCMS model, our aim is to identify differentially spliced genes that may have contributed to the observed abnormalities in the axial skeleton. Preliminary results from bulk RNA sequencing of somite in early-stage (E9.5) mutants revealed abnormal splicing and expression of genes essential for axial skeletal development. Future work will focus on the contribution of abnormal splicing and expression of these genes to rib abnormalities found in CCMS.
