Molecular mechanisms underlying the mitosisYmeiosis decision
Yuriko Harigaya & Masayuki Yamamoto*
Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, 113-0033, Japan; Tel: +81-35-8414386; Fax: +81-35-802-2042;
Key words: cell cycle regulation, fission yeast, mRNA elimination, nutrition, pheromone signaling,
Most eukaryotic cells possess genetic potential to perform meiosis, but the vast majority of them never initiate it.
The entry to meiosis is strictly regulated by developmental and environmental conditions, which vary
significantly from species to species. Molecular mechanisms underlying the mitosisYmeiosis decision are unclear
in most organisms, except for a few model systems including fission yeast Schizosaccharomyces pombe. Nutrient
limitation is a cue to the entry into meiosis in this microbe. Signals from nutrients converge on the activity of
Mei2 protein, which plays pivotal roles in both induction and progression of meiosis. Here we outline the current
knowledge of how a set of environmental stimuli eventually activates Mei2, and discuss how Mei2 governs the
meiotic program molecularly, especially focusing on a recent finding that Mei2 antagonizes selective elimination
of meiotic messenger RNAs.
Meiosis is a process for forming haploid gametes
from diploid germ cells, which is essential for
sexually reproducing species to transmit genetic
information to the next generation. Meiosis drives a
specialized cell cycle that consists of one round of
DNA synthesis followed by two successive rounds of
M phase. This procedure, which halves the genetic
material, seems to be highly conserved in eukaryotes.
However, cues that cause cells to enter the meiotic
pathway appear to vary greatly among species. In
multicellular organisms, extrinsic cues from sur-
rounding cells control the differentiation of germline
stem cells that will enter the meiotic cell cycle. In
lower eukaryotes such as budding yeast Saccharomy-
ces cerevisiae or fission yeast Schizosaccharomyces
pombe, a reduction of available nutrition in the
environment triggers the entry into the meiotic cell
cycle. In either case, the decision to enter the meiotic
cell cycle is tightly regulated in order to prevent
execution of the meiotic program in inappropriate
developmental contexts. Here, we discuss controls to
commit cells to meiosis in fission yeast, which is an
excellent model system for study of the mito-
sisYmeiosis decision. Our discussion focuses on the
regulatory pathways underlying the two types of cell
Meiotic differentiation includes complex sequen-
tial events. Yeast meiosis may be conventionally
divided into two parts: (1) exit from the mitotic cell
cycle and (2) induction of the alternate, meiotic cell
cycle program, in which mitotic events may occur in
a peculiar manner and order. The former process in
fission yeast has been characterized as a multilayered
network of positive and negative factors, which are
Chromosome Research (2007) 15:523–537
regulated at various levels of gene expression from
transcription initiation to protein modification and
degradation (Yamamoto 1996, 2004, Yamamoto
et al. 1997). The network also involves many
feedback loops to intensify the commitment to
meiosis, which may ensure that mitosis and meiosis
become mutually exclusive. In contrast, the latter
process has been less characterized, although it is
generally assumed to be achieved by a highly
coordinated transcriptional induction of numerous
genes that are specifically required for meiosis (Mata
et al. 2002). The meiosis-specific gene products are
likely to be required (1) to modify the basic cell
duplication machinery that operates in the mitotic
cell cycle, so that DNA synthesis followed by two
successive nuclear divisions will be ensured and
(2) to reorganize the cell morphology, which results
in the formation of asci containing four haploid
spores, the counterparts of gametes in higher eukar-
yotes. In the next four sections we will describe the
developmental fates available for fission yeast cells
and overview the current knowledge of cell cycle
regulation and gene expression during mitosis and
meiosis in this microbe. We will then look at key
focusing on how the exit from the mitotic cell cycle
and the initiation of the meiotic program are governed
by this system. Finally, we will address how the envi-
ronmental cues convey a signal to the key factors and
regulate the exit from the mitotic cell cycle.
Developmental fates of fission yeast
Under conditions rich in nutrition, fission yeast cells
proliferate through mitotic cell cycles, mainly as
haploids, which carry one of the two mating types
denoted as h+(P) and hj(M). As in higher
eukaryotes, the mitotic cell cycle can be divided into
four phases, namely G1, S, G2, and M. Mitotic cells
assume one of the three alternative fates according to
the environmental conditions: They may (1) continue
to progress through the mitotic cell cycle, (2) enter
into the quiescent stationary phase, or (3) differenti-
ate into the conjugation/meiosis pathway. Fission
yeast cells can enter the stationary phase from either
mitotic G1 or G2. Different environmental stimuli
impose different effects on the mitotic cell cycle.
Glucose starvation, for example, primarily arrests
proliferating cells in G2 and lead them to the
stationary phase (Costello et al. 1986). Under
nitrogen starvation, in contrast, haploid cells arrest
in G1and enter the stationary phase, usually after
performing two or three rounds of rapid mitotic
cycle. If cells of the opposite mating type are
neighboring under nitrogen starvation, haploid cells
mate to form zygotes, which subsequently undergo
meiosis and generate four haploid spores. Impor-
tantly, only haploid cells in G1phase can initiate the
conjugation process. Zygotes can grow as diploids if
they are transferred to a rich medium immediately
after conjugation. These diploid cells undergo meio-
sis and form spores when they exhaust the available
nutrients. Whether they are zygotes or diploids,
meiotic cells follow essentially the same pathway.
They arrest transiently in G1, initiate one round of
DNA synthesis, and perform two consecutive nuclear
divisions, called first and second meiotic divisions
(alternatively, meiosis I and meiosis II). Importantly
also, only G1-arrested diploid cells can enter the
Cell cycle regulation during mitosis
During the mitotic cell cycle, the onset of S phase
and that of M phase are under tight regulation, in
order to ensure that these two phases are coupled in
the correct order (reviewed in MacNeill & Nurse
1997, Moser & Russell 2000). The major player in
this control is Cdc2, the cyclin-dependent kinase
(CDK), whose activity is low in G1phase, moderate
during S phase and G2phase, and high during M
phase. Cdc2 is associated with cyclin Cig2 at the
G1/S transition (Bueno & Russell 1993, Connolly &
Beach 1994, Obara-Ishihara & Okayama 1994).
Deletion of cig2 delays entry to S phase, but does
not completely block the transition, because mitotic
cyclin Cdc13 can eventually substitute the function
of Cig2 (Fisher & Nurse 1996). The entry to S phase
also requires the function of Cdc10, which consti-
tutes a transcription factor complex called DSC1
(Lowndes et al. 1992). The DSC1 complex is thought
to contain Cdc10, Res1, Res2, and Rep2 to mediate
G1/S specific transcription through both stimulatory
and repressive functions (Tanaka et al. 1992:
Caligiuri & Beach 1993, Miyamoto et al. 1994,
Y. Harigaya & M. Yamamoto
Zhu et al. 1994, Nakashima et al. 1995, Baum et al.
1997, Whitehall et al. 1999). The DSC1 targets
include genes essential for DNA replication, such as
cdc18 encoding a fission yeast homolog of conserved
replication factor Cdc6, cdt1 encoding another
conserved replication factor, and cdc22 encoding
ribonucleotidereductase(Kellyet al. 1993, Fernandez-
Sarabia et al. 1993, Hofmann & Beach 1994, White
et al. 2001). The onset of mitosis is driven by the
Cdc2YCdc13 complex, which is regulated positively
by the Cdc25 phosphatase and negatively by the
Wee1 and Mik1 kinase (Lundgren et al. 1991, Millar
et al. 1991). E3 ubiquitin ligase APC/C (anaphase-
promoting complex/cyclosome) associated with its
activator Slp1 (APC/CSlp1) is required for Cdc13 deg-
radation upon exit from M phase, whereas APC/C
associated with another activator Ste9 (APC/CSte9)
and the CDK inhibitor (CKI) Rum1 are responsible
for suppressing Cdc2 activity during G1 phase
(Correa-Bordes & Nurse 1995, Yamaguchi et al.
1997, Kitamura et al. 1998, Blanco et al. 2000).
An important concept in the yeast cell cycle is
FStart_, which is a point (or an interval) during G1at
which the cell becomes committed to the mitotic cell
cycle. Prior to passing Start, cells have the potential
to take the three alternative developmental programs
mentioned above. At Start, cells carefully monitor
their own size and nutritional conditions and deter-
mine their fate. The transition at G2/M is another
control point in the mitotic cell cycle, where again
both size and nutritional controls are in operation.
Cell cycle regulators relevant to the switch between
the mitotic and meiotic cell cycles are shown
schematically in Figure 1. Regulation by TOR
complex TORC1, included in this figure, will be
discussed at the end of this review.
Cell cycle regulation during meiosis
It has been suggested that Cdc2 kinase plays essential
roles in driving the meiotic cell cycle. Genetic
analyses have established the absolute requirement
of the cdc2 gene for the meiotic G1/S transition and
the second meiotic division (Iino et al. 1995). Cdc2
cooperates with cyclin Cig2 to launch premeiotic S
phase (Borgne et al. 2002). Cyclin Cdc13 and the
CDK activator Cdc25 are required for both the first
and second meiotic divisions (Iino et al. 1995)
(Figure 1). During premeiotic S phase, transcription
of two groups of genes are simultaneously activated:
(1) a group that is also expressed in the mitotic G1/S
interval and required for DNA synthesis (e.g., cdc18,
cdt1, and cdc22) and (2) a group that is specific to
meiosis, including the rec genes (e.g., rec8 and
rec11) involved in meiotic recombination (Fox &
Smith 1998, Watanabe et al. 2001, Mata et al. 2002).
Genes of both groups appear to be regulated by the
DSC1 complex, which is responsible for the tran-
scriptional activation of the former class of genes in
mitotic cells (White et al. 2001, Cunliffe et al. 2004).
It is proposed that a meiotic form of DSC1,
containing Cdc10, Res2, and a meiosis-specific
component Rep1, is responsible for the meiotic
pattern of gene expression (Sugiyama et al. 1994).
The meiosis-specific S phase transcription may lead
to a peculiar mode of DNA synthesis coupled with
incorporation of a meiosis-specific cohesin complex
(Watanabe et al. 2001) and recombination at a high
frequency, eventually followed by two consecutive
Classical genetic analyses have identified meiotic
mutants that arrest at a specific point in the meiotic
cell cycle (reviewed in Yamamoto et al. 1997). The
mei2, mei3, and mei4 mutants arrest with a single
nucleus in the cell, whereas the mes1 mutants arrest
with two nuclei, indicating cell cycle arrest before
the second meiotic division. The mei2 and mei3
mutants fail to proceed to premeiotic S phase,
whereas the mei4 mutant arrests before the first
meiotic division after completing DNA synthesis.
One possible function of these gene products is to act
on cell cycle machineries that are utilized also in the
mitotic cell cycle. Indeed, emerging evidence sup-
ports this idea with regard to mei4 and mes1. mei4
encodes a transcription factor that is required for
transcriptional activation of cdc25 during meiosis, in
addition to numerous other target genes (Iino et al.
1995, Horie et al. 1998, Mata et al. 2002) (Figure 1).
Lowered Cdc25 activity presumably explains the cell
cycle arrest in the mei4 mutant, because artificial
expression of cdc25 restores meiotic divisions in the
mei4D cells (H. Murakami, personal communica-
tion). Mes1 binds and inhibits the APC/C activator
Slp1, and hence secures the Cdc2YCdc13 MPF
activity to carry out the second meiotic division
(Izawa et al. 2005). Meanwhile, mei3 is required to
activate the mei2 gene product, Mei2, which is the
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The mitosisYmeiosis decision