Insights into the function of SOX9 and campomelic dysplasia

Abstract

Human SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia (CD). Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation. Studies in zebrafish and Xenopus suggest that Sox9 may be crucial for specification of the otic placode. In mice, loss of Sox9 results in failure of otic placode invagination. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a later morphogenetic role but phenotypic details are limited. Sox9-/- null mice die before morphogenesis of the inner ear is complete, precluding investigation of the role of Sox9 later in ear development. Because all the SOX9 mutations are heterozygous and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act dominant negatively by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. To assess whether such mutations in SOX9 may act via a dominant interference mechanism we generated transgenic and conditional knock’in mice expressing a mouse equivalent of a CD mutation, a Y440X nonsense mutation causing premature termination within the trans-activation domain of SOX9 (Sox9Y440X). Our data reveal an essential role for Sox9 for sensory and non-sensory morphogenesis of the inner ear. We compared the phenotypic impact of the Sox9 Y440X mutation with a Sox9 null mutation. These studies point to context dependent mechanisms for the Y440X nonsense mutation.