Role of SoxC transcription factors in nervous system development
Transcription factors of the Sox family are important developmental regulators. They contain a high-mobility-group box as sequence-specific DNA-binding domain. The twenty mammalian Sox proteins can be subdivided into 10 groups according to sequence homology. We analyse the functions of the groupC proteins Sox4, Sox11 and Sox12 in nervous system development. The three proteins are highly homologous and show similar DNA binding properties and transactivation potential in vitro. All SoxC proteins are widely and dynamically expressed during mouse embryogenesis and are associated with many inductive and remodeling processes during vertebrate tissue and organ development. They are also involved in many diseases and regenerative processes, most prominently in tumor formation and progression. Expression patterns of the three proteins show extensive overlap complicating determination of developmental roles. The corresponding mouse mutants have revealed essential developmental functions for Sox4 and Sox11. Sox4 is required for heart and outflow tract formation, B cell development, T cell differentiation, pancreas and skeletal development. We could show that Sox11 is likewise involved in heart and outflow tract formation, and has additional roles in skeletal development, spleen formation and the developing anterior eye segment. Both deficiencies are lethal. Our analysis of Sox12-deficient mice, in contrast, revealed no overt phenotypic abnormalities.
Despite the well documented expression patterns, analyses of mouse mutants with single SoxC gene deficiencies have failed to reveal major defects in nervous system development. This absence of overt neural phenotypes has led to the assumption that SoxC proteins may function redundantly during nervous system development so that their role may only become evident in mice with multiple SoxC gene deficiencies.
Our goal is to unravel SoxC functions in the nervous system using conditional mouse mutagenesis, gene knock-down and overexpression strategies in the chicken embryo, as well as tissue culture and molecular biology methods.
Recently, we could show for the sympathetic nervous system that in the absence of both Sox4 and Sox11, sympathetic ganglia remain hypoplastic throughout embryogenesis because of consecutive proliferation and survival defects of sympathetic neurons. As a consequence, sympathetic ganglia are rudimentary in the adult and sympathetic innervation of target tissues is impaired leading to severe dysautonomia.