Kinetoplast DNA Network: Evolution of an Improbable Structure

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Abstract
Cryptococcus neoformans is a pathogenic fungus with a defined sexual cycle involving haploid MATα and MATa cells. Interestingly, MATα strains are more common, are more virulent than congenic MATa strains, and undergo haploid fruiting in response to nitrogen limitation or MATa cells. Three genes encoding the MFα pheromone were identified in the MATα mating-type locus and shown to be transcriptionally induced by limiting nutrients and coculture with MATa cells. The MFα1, MFα2, and MFα3 genes were mutated, individually and in combination. MATα strains lacking MFα pheromone failed to induce morphological changes in MATa cells. Pheromoneless MATα mutants were fusion and mating impaired but not sterile and mated at ∼1% the wild-type level. The pheromoneless MATα mutants were also partially defective in haploid fruiting, and overexpression of MFα pheromone enhanced haploid fruiting. Overexpression of MFa pheromone also enhanced haploid fruiting of MATα cells and stimulated conjugation tube formation in MATa cells. A conserved G-protein activated mitogen-activated protein kinase signaling pathway was found to be required for both induction and response to mating pheromones. The MFα pheromone was not essential for virulence of C. neoformans but does contribute to the overall virulence composite. These studies define paracrine and autocrine pheromone response pathways that signal mating and differentiation of this pathogenic fungus.