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Eukaryotic Cell, June 2002, p. 366-377, Vol. 1, No. 3
1535-9778/02/$04.00+0     DOI: 10.1128/EC.1.3.366-377.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pheromones Stimulate Mating and Differentiation via Paracrine and Autocrine Signaling in Cryptococcus neoformans

Wei-Chiang Shen,1,{dagger} Robert C. Davidson,1 Gary M. Cox,2,3 and Joseph Heitman1,2,3,4,5*

Departments of Genetics,1 Medicine,2 Microbiology,3 Pharmacology and Cancer Biology,4 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 277105

Received 14 December 2001/ Accepted 1 March 2002

Cryptococcus neoformans is a pathogenic fungus with a defined sexual cycle involving haploid MAT{alpha} and MATa cells. Interestingly, MAT{alpha} 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 MF{alpha} pheromone were identified in the MAT{alpha} mating-type locus and shown to be transcriptionally induced by limiting nutrients and coculture with MATa cells. The MF{alpha}1, MF{alpha}2, and MF{alpha}3 genes were mutated, individually and in combination. MAT{alpha} strains lacking MF{alpha} pheromone failed to induce morphological changes in MATa cells. Pheromoneless MAT{alpha} mutants were fusion and mating impaired but not sterile and mated at ~1% the wild-type level. The pheromoneless MAT{alpha} mutants were also partially defective in haploid fruiting, and overexpression of MF{alpha} pheromone enhanced haploid fruiting. Overexpression of MFa pheromone also enhanced haploid fruiting of MAT{alpha} 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 MF{alpha} 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.

* Corresponding author. Mailing address: Department of Genetics, 322 Carl Building, Box 3546, Duke University Medical Center, Research Dr., Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

{dagger} Present address: Department of Plant Pathology, National Taiwan University, 106 Taipei, Taiwan.

Eukaryotic Cell, June 2002, p. 366-377, Vol. 1, No. 3
1535-9778/02/$04.00+0     DOI: 10.1128/EC.1.3.366-377.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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