Targets of the Sex Inducer homeodomain proteins are required for fungal development and virulence in Cryptococcus neoformans.

In the yeast Saccharomyces cerevisiae, the regulation of cell types by homeodomain transcription factors is a key paradigm; however, many questions remain regarding this class of developmental regulators in other fungi. In the human fungal pathogen Cryptococcus neoformans, the homeodomain transcription factors Sxi1α and Sxi2a are required for sexual development that produces infectious spores, but the molecular mechanisms by which they drive this process are unknown. To better understand homeodomain control of fungal development, we determined the targets of the Sxi2a-Sxi1α heterodimer using whole genome expression analyses paired with in silico and in vitro binding site identification methods. We identified Sxi-regulated genes that contained a site bound directly by the Sxi proteins that is required for full regulation in vivo. Among the targets of the Sxi2a-Sxi1α complex were many genes known to be involved in sexual reproduction, as well as several well-studied virulence genes. Our findings suggest that genes involved in sexual development are also important in mammalian disease. Our work advances the understanding of how homeodomain transcription factors control complex developmental events and suggests an intimate link between fungal development and virulence.