Fission yeast as a model organism – Department of Biology - University of Copenhagen

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Fission Yeast - a Model Worthy of Pursuit

The genus Schizosaccharomyces (fission yeasts) is deeply rooted among ascomycetous fungi. Comprising but three peculiar species, it is known to descriptive science for more than 100 years. Just one of these, S. pombe, has been subject to extensive experimental research for some 50 years and, thus, has become virtually synonymous with "fission yeast" (two cousin species are S. octosporus and S. japonicus). S. pombe has indeed become one of the best known model organisms in the entire fungal kingdom - only next to baker's yeast (Saccharomyces cerevisiae). As fungi share a common ancestor with the animal kingdom  and the fungal-specific specializations of fission yeast are relatively few, much of basic cell biology observed in S. pombe is also relevant for basic mechanisms at work in animal cells.

  In the early 1950ies, two eminent and farsighted biologists began to study S. pombe - independently and for quite different reasons - and their studies have become very complementary indeed. In Edinburgh, the dedicated physiologist Murdoch Mitchison wanted to study the mechanisms and kinetics of growth, since dividing cells usually have to grow before they can divide again. The rod-shaped cells of fission yeast served his purpose well. Their cell diameter being constant, he could simply measure increments in length instead of volume, following single cells in time-lapse movies, or studying synchronized cultures in bulk. With no recourse to genetics, however, only limited knowledge could be gained from wild-type cell cultures in this regard.

  In Zürich and Berne, on the other hand, Urs Leupold was looking for a simple eukaryotic organism to study basic mechanisms of genetics - with little distraction from complex patterns of differentiation, as commonly associated with the life-cycles of multicellular eukaryotes. Thus, he came to Copenhagen for guidance and advice from Øjvind Winge (the father of budding yeast genetics), and he was captivated by the four-spored asci of the fission yeast S. pombe, which were abundant at the end of growth of haploid cell cultures, when transiently diploid zygotes underwent meiotic sporulation right away. The linear arrangement of the four meiospores could potentially allow access to studying the mechanisms of meiosis more easily than what appeared possible in other model organisms. Yet, to mobilize this potential, Urs Leupold had first to build up the genetic infrastructure of this newly emerging model system: (i) characterizing the various mating-types for doing controlled genetic crosses, (ii) setting up standard conditions for doing genetic crosses in the lab, and (iii) isolating suitable mutants to be subjected to experimental crosses. Urs Leupold and his group managed to set up all three of these preconditions, and by 1970 a handful of other groups had joined in, concentrating on genetic phenomena of basic interest, such as mitotic and meiotic recombination, spontaneous and induced mutagenesis, nonsense-suppressing tRNAs, a few selected biochemical pathways, and mitochondrial genetics.

  A great leap forward was taken by Paul Nurse in the early 1970ies by successfully merging Leupold's genetic tools and methods with Mitchison's cell cycle work and pending problems. By isolating cell cycle mutants and pioneering molecular technology of reverse genetics in fission yeast he actively transformed S. pombe into a forefront model system. For the characterization of cyclin-dependent protein kinases as key players in driving the cell cycle across major transition points - from G1 into S-phase and from G2 into mitosis - Paul Nurse was awarded the 2001 Nobel Prize in Physiology or Medicine, together with Tim Hunt and Lee Hartwell.

  The sequencing of the fission yeast genome by 2002 was another important landmark, which attracted many new research groups into working with the S. pombe homologs of their favorite gene(s) from other organisms. It had become clear before that the most popular model system for eukaryotic molecular cell physiology, Saccharomyces cerevisiae, had certain shortcomings in its comparative potential - due to the evolutionary specialization of budding yeasts in general. The genomes of this diverse and successful group of  eukaryotic microorganisms have been subject to streamlining at various levels. Numerous genes have been lost (~300), often in composite interactive groups, which else are widely conserved in other eukaryotes. Such functional subsystems - still present in fission yeast, but absent or nearly so in budding yeast - comprise the signalosome, many spliceosome components, the exon junction complex, composite centromeres with pericentromeric heterochromatin, heterochromatin silencing components, including the RNAi processing machinery, etc.

  Hence, these differentially conserved aspects of fission yeast molecular biology have attracted particular attention among contemporary research groups. In addition, other basic processes and mechanisms, which at least in part are shared with budding yeast, are actively being investigated as well, and many interesting differences  have surfaced in detail from these analyses. Some highlights of this research comprehend microtubule dynamics in mitotis and interphase, checkpoints and origin firing in DNA replication, chromosome cohesion and segregation, actomyosin involvement in cytokinesis, DNA repair pathways, mitotic and meiotic recombination, the involvement of specialiced recombinational components in the intricate system of mating-type switching, signal transduction in nutritional sensing and in sexual differentiation, the complex program of meiosis and sporulation, and many others not listed here.

  For all its modelling potential, S. pombe is also a living organism uniquely shaped by evolution, and curiosity-driven research has come up with charming surprises. For example, the meiotic program exclusively uses one of two pathways of meiotic crossing-over, which in many other organisms occur side by side. In fact, S. pombe has become very efficient in utilizing the minor one of these and has lost the genes for the commonly prevailing pathway altogether. Hence, there is no bivalent synapsis by synaptonemal complexes and no crossover interference either. Instead, the lack of synapsis is compensated for by another conserved feature of canonical meiosis, the clustering of telomeres in the so-called bouquet arrangement. This is vastly exaggerated in a series of nuclear movements, which in S. pombe facilitate a dynamical alignment of homologous chromosomes throughout meiotic prophase. With only three pairs of chromosomes of different lengths, this appears to work surprisingly well. - Also, the main recombinational intermediates in S. pombe consist of single Holliday junctions, whilst earlier results on S. cerevisiae had suggested double Holliday junctions as the canonical model.

  Moreover, certain genes originally needed for homologous recombination and repair have been co-opted by fission yeast for its peculiar system of mating-type interconversion, and some of these recombinational functions were first recognized by genetic mutations affecting mating-type switching. {In evolutionary science, co-option is used when natural selection develops new uses for pre-existing traits.} On similar terms, a chunk of pericentromeric heterochromatin and various gene functions involved in heterochromatin organization have been co-opted for the transcriptional silencing of the backup copies of mating-type genes that are necessary for homothallic mating-type switching. Again, several mutations affecting centromere organization were first detected by their effects on mating-type expression.

  On skimming over the S. pombe genome database, the number of annotated genes for conserved proteins without a characterized function is still remarkably high. This is but one indication that the heydays of using fission yeast as a model organism in molecular genetics are not over yet. More recently, the cousin genomes of S. octosporus and S. japonicus are also being sequenced, which will considerably broaden the comparative potential of fission yeast research. S. japonicus, in particular, can readily alternate between yeast cells and invasive, hyphal growth  - as a desirable model system for bimodal growth, which in various pathogenic fungi is of medical importance.

Richard Egel
professor emeritus {professor of genetics 1978-2004}
Department of Molecular Biology, University of Copenhagen Biocenter, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark