Gli-mediated regulation of Sox9 in limb development

Abstract

The transcription factor SOX9 is essential for skeletogenesis and heterozygous mutations in the gene cause Campomelic Dysplasia (CD). Recently, chromosomal aberrations at >1Mb from SOX9 coding region have been detected in some CD patients, suggesting the requirement of long-range regulatory elements in controlling the precise expression of SOX9 for proper skeletal development. However, the exact identities of these elements or the transcription factors that direct appropriate expression of SOX9 are unknown. Here, we identified nine conserved putative enhancers of SOX9. Molecular and genetic analyses suggest Shh-Gli pathways as potential upstream regulatory networks that govern the spatiotemporal and dosage of limb Sox9 expression via predicted enhancers. Our study will provide novel insights on molecular mechanism governing the complex patterning of Sox9 in the developing limb, and the disease mechanisms of CD.