Meiosis-specific genes play roles in ploidy reduction in Cryptococcus neoformans titan cells
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Cryptococcus neoformans is a fungal pathogen of humans that causes life-threatening meningoencephalitis. During infection, enlarged, polyploid titan cells are produced that promote survival, evade immune cells, and generate diverse progeny. These titan cells divide to produce haploid, aneuploid or diploid daughter cells with enhanced stress tolerance; however, how ploidy reduction occurs is poorly understood. Here, we show that titan cells developed from diploid strains predominantly produce diploid daughter cells with haploid daughters observed infrequently. We further demonstrate that meiosis-specific genes, including DMC1 and SPO11 , are critical for stable inheritance of a diploid genome in the daughter cells. Specifically, deletion of these genes in a heterozygous diploid background results in: 1) titan cells with a significantly reduced capacity to produce daughter cells; 2) increased phenotypic variation among daughter cells produced by the titan cells, including traits that could be relevant to cell growth and viability; and 3) daughter cells produced by the titan cells exhibiting high levels of loss of heterozygosity (LOH) and aneuploidy, suggested elevated genome instability. Taken together, these findings demonstrate the importance of meiosis-specific genes in the ploidy reduction process of titan cells derived from a heterozygous diploid background in an important human fungal pathogen.
SIGNIFICANCE
Polyploid titan cells are central to Cryptococcus neoformans persistence during infection, yet how they reduce ploidy to generate daughter cells was unclear. We show that the meiosis-specific factors Dmc1 and Spo11 are critical for titan cells to produce viable daughter cells specifically in a heterozygous diploid context, ensuring chromosome stability without introducing detectable canonical meiotic recombination. Loss of either gene compromises daughter cell production and causes genome instability (LOH, aneuploidy) and phenotypic heterogeneity. These findings reveal a “para-meiosis” safeguard that preserves genome balance during titan cell depolyploidization in C. neoformans .