Scoliosis, the most common type of spine deformity in children, occurs in around 1-3% of the population worldwide and 90% of those patients that develop a severe curvature are female. The most common form of scoliosis is adolescence idiopathic scoliosis (AIS), which occurs in otherwise healthy children with no obvious structural problems with the spine. The biological origin of AIS is poorly understood. We will use mouse models to understand AIS pathogenesis at the molecular and cellular level.
Many AIS-associated single nucleotide polymorphism (SNP) regions identified in previous GWAS studies are located within non-coding sequences near the Lbx1 gene. Lbx1 is an evolutionally conserved transcription factor essential for normal embryonic development, with roles in muscle development and the specification of dorsal spinal cord somatosensory interneurons. We investigated the function of Lbx1 by determining the direct targets of Lbx1 in the developing mouse spine, using chromatin-immunoprecipitation followed by sequencing (ChIP-seq). Over 2000 potential direct targets for Lbx1 were identified and are currently being validated using a CRISPR-CAS9 Lbx1 deletion mouse line. Gene ontology analysis revealed significant enrichment for genes involved in neurogenesis, axon guidance and cell migration consistent with a role for Lbx1 in determining neuronal cell fate in the spinal cord. Lbx1 target genes include several other genes previously linked to AIS, suggesting molecular pathways that may lead to AIS susceptibility.