Abstract
Cryptococcus neoformans is a human fungal pathogen that undergoes a dimorphic transition from a unicellular yeast to multicellular hyphae during opposite sex (mating) and unisexual reproduction (same-sex mating). Opposite- and same-sex mating are induced by similar environmental conditions and involve many shared components, including the conserved pheromone sensing Cpk1 MAPK signal transduction cascade that governs the dimorphic switch in C. neoformans. However, the homeodomain cell identity proteins Sxi1α/Sxi2a encoded by the mating type locus that are essential for completion of sexual reproduction following cell–cell fusion during opposite-sex mating are dispensable for same-sex mating. Therefore, identification of downstream targets of the Cpk1 MAPK pathway holds the key to understanding molecular mechanisms governing the two distinct developmental fates. Thus far, homology-based approaches failed to identify downstream transcription factors which may therefore be species-specific. Here, we applied insertional mutagenesis via Agrobacterium-mediated transformation and transcription analysis using whole genome microarrays to identify factors involved in C. neoformans differentiation. Two transcription factors, Mat2 and Znf2, were identified as key regulators of hyphal growth during same- and opposite-sex mating. Mat2 is an HMG domain factor, and Znf2 is a zinc finger protein; neither is encoded by the mating type locus. Genetic, phenotypic, and transcriptional analyses of Mat2 and Znf2 provide evidence that Mat2 is a downstream transcription factor of the Cpk1 MAPK pathway whereas Znf2 functions as a more terminal hyphal morphogenesis determinant. Although the components of the MAPK pathway including Mat2 are not required for virulence in animal models, Znf2, as a hyphal morphology determinant, is a negative regulator of virulence. Further characterization of these elements and their target circuits will reveal genes controlling biological processes central to fungal development and virulence.
Highlights
Many fungi undergo dramatic morphological differentiation during their life cycles
The mitogenactivated protein kinase (MAPK) cascade regulating the dimorphic switch in S. cerevisiae, often referred to as the pheromone response pathway, provides a framework for studying morphogenesis in a variety of fungal species, including the human fungal pathogen Cryptococcus neoformans [1,2,3,4,5]
Sexual reproduction typically involves partners of opposite mating type, sex can occur with just one mating type and even with single individuals
Summary
Many fungi undergo dramatic morphological differentiation during their life cycles. The morphological transition between the yeast form and the pseudohyphal form during mating and invasive growth in Saccharomyces cerevisiae has served as a paradigm for developmental biology due to the well-characterized genetics and robust molecular tools in this organism. Homologs of the core components of the MAPK cascade are conserved among evolutionarily distantly related fungi. The downstream targets of the MAPK cascade, which are effectors that evoke species-specific adaptive responses to external or internal signals, are often not conserved. The identity of the downstream transcription factors that activate or repress corresponding target genes in different species are often difficult to reveal through a candidate gene approach
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