Adolescent Idiopathic Scoliosis (AIS) is a 3-Dimensional rotational curvature of the spine. Affecting between 1-4% of the population, onset typically coincides with puberty in otherwise health individuals. A key characteristic of AIS is an overwhelming sex-bias, 90% of progressive cases are female with no known explanation. Genome wide association studies have recently identified the transcription factor gene, Lbx1, as a candidate gene for AIS. Lbx1 is the only consistently replicated finding across multiple ethnic groups. Lbx1 has a role in spinal cord development, specifying dorsal horn interneuron populations during embryo development. However, how Lbx1 is linked to AIS susceptibility and progression in females is unknown.
We propose a sex-specific interaction between genetic susceptibility and female-specific hormonal changes occurring through puberty. RNA-sequencing was initially conducted to identify any significantly differentially expressed genes in spinal cords from juvenile and adult mice. A total of 382 differentially expressed genes were identified. Ten genes of interest were selected (that were also predicted target genes of Lbx1), and RT-qPCR was used to determine their expression in male and female mice before and after puberty. Subsequent studies into sex-specific interactions occurring across puberty were examined in gonadectomy experiments, with and without hormonal replacement. Together these experiments suggest expression of Lbx1 and downstream targets are altered in response to gonadal hormones.
Future steps will involve determining the function of Lbx1 in the juvenile mouse spinal cord and the generation of a mouse model of AIS (not currently available) using CRISPR-Cas9 gene editing.