Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, 5007 Rockhill Rd, Kansas City, MO 64112, USA
* Author for correspondence (e-mail: honigbergs{at}umkc.edu)
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Summary |
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Key words: IME1, IME2, Mitosis, Meiosis, Cell cycle, Sporulation, Signal code
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Introduction |
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Here we review recent progress in understanding the nutritional control of
meiotic initiation in S. cerevisiae with particular focus on how
distinct nutritional signals are integrated together into a signaling network.
Nutrients also control pseudohyphae formation in this yeast
(Gancedo, 2001;
Pan et al., 2000
;
Rua et al., 2001
;
Wendland, 2001
), but this
alternative form of cell differentiation is beyond the scope of this
Commentary. Similarly, because our focus is on nutritional controls, other
controls of meiosis, such as checkpoint controls on the meiosis I division
(Murakami and Nurse, 2000
;
Roeder and Bailis, 2000
), will
be discussed only briefly. Although we concentrate on S. cerevisiae,
we also discuss some differences between the signaling network controlling
meiotic initiation in this yeast and the analogous signaling network in
another yeast, S. pombe.
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Nutritional signals controlling initiation of meiosis in diploid yeast |
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For S. cerevisiae to enter meiosis, its nutritional environment must meet three criteria. First, the environment must lack at least one essential growth nutrient (nitrogen limitation is commonly used in the laboratory), which causes the cells to arrest in G1 phase. Second, the environment must contain a non-fermentable carbon source, which can be metabolized through respiration. Third, glucose must be absent from the environment; glucose inhibits meiotic initiation even when the other two criteria are met.
In other yeast species, initiation of meiosis is regulated by nutritional
signals different from those that regulate S. cerevisiae. For
example, in Candida lusitaniae, meiosis and sporulation occur in the
presence, but not in the absence, of glucose
(Francois et al., 2001). In
many yeasts, such as Candida albicans, laboratory conditions that
promote meiosis have not been identified
(Odds et al., 2000
). In
contrast, the nutritional criteria for initiation of meiosis in
Schizosaccharomyces pombe are well understood, and these criteria
differ in several ways from those controlling meiotic initiation in S.
cerevisiae (reviewed in Yamamoto,
1996
). First, S. cerevisiae haploids conjugate under
growth conditions and then fuse to form stable diploids, whereas S.
pombe haploids conjugate under starvation conditions to form diploids
that immediately undergo meiosis and sporulation. Second, in S.
pombe, the environmental signals that trigger the sexual cycle are
nitrogen starvation and cellular stress. As discussed below, differences
between nutritional controls on meiotic initiation in S. cerevisiae
and S. pombe are attributable to differences in the signaling
networks in these two yeast species.
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The targets of nutritional regulation of meiotic initiation |
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Regulation of IME1 signal integration at a complex
promoter
Different signaling pathways can be integrated by jointly controlling
transcription of the same gene (Ptashne
and Green, 2002). IME1, like other yeast genes with key
regulatory roles, has a larger than average regulatory region (approximately 2
kb) (Granot et al., 1989
;
Rupp et al., 1999
). For yeast
genes, the entire regulatory region is termed the promoter. The IME1
promoter can be subdivided into four contiguous regions, upstream control
regions 1-4 (UCS1-4), and contains a number of separate regulatory elements
within these regions (Sagee et al.,
1998
). Several of these elements respond to particular nutritional
signals (Fig. 1A). For example,
glucose represses IME1 through the 32 bp IREu site, which is
approximately 1100 bp upstream from the ORF, whereas acetate activates
IME1 through the UASrm site, which is 800 bp upstream of the ORF
(Sagee et al., 1998
).
|
IME1 is fully repressed in growing cells, but, once cells cease
growth, it is expressed at a moderate level. Further induction of
IME1 can be prevented by either the presence of glucose or the
absence of a non-fermentable carbon source in the nutrient environment
(Purnapatre et al., 2002).
Because glucose is converted into ethanol at late stages of growth (this is
termed the diauxic shift), cells at late stages are primed to initiate
meiosis. The diauxic shift may explain why meiosis occurs only at a specific
time as yeast colonies mature and preferentially at the edge of these colonies
rather than at their centers (Purnapatre
and Honigberg, 2002
). Most of the growth in a maturing yeast
colony occurs at its edge (Meunier and
Choder, 1999
); so conversion of glucose to ethanol as cells at the
periphery of mature colonies become limited for nutrients may provide all the
signals necessary for full IME1 induction.
Cell type and nutritional signals regulate IME1 transcription
through distinct regions of the IME1 promoter. Cell-type control
ensures that IME1 is not induced in haploid cells under any
nutritional conditions. The primary region of the IME1 promoter
required for cell-type control (UCS3 and UCS4) does not overlap with the
regions required for nutritional regulation (UCS1 and UCS2)
(Covitz and Mitchell, 1993;
Sagee et al., 1998
). Rme1p, a
transcription factor expressed to much higher levels in haploids than
diploids, represses IME1 through at least two different mechanisms.
First, Rme1p binds to the RRE1 site within the UCS4 of IME1 to
directly repress IME1 transcription. Second, Rme1p binds to a similar
site in the promoter of CLN2, which encodes a G1 cyclin, to activate
its transcription (Blumental-Perry et al.,
2002
; Frenz et al.,
2001
). As discussed below, expression of Cln2p inhibits
IME1 expression.
There is no IME1 ortholog in S. pombe; instead
nutritional signals regulate ste11+ transcription to
control entry into the sexual cycle. Like IME1, ste11+
encodes a transcription factor, but because conjugation and meiosis are linked
processes in S. pombe, Ste11 activates genes required for conjugation
before it activates genes required for meiosis. Transcription of
ste11+ is activated by nitrogen starvation and cellular
stress through two transcription factors, Atf1-Pcr1 and Rts2, which bind to
the ste11+ promoter
(Higuchi et al., 2002;
Kunitomo et al., 2000
). Once
genes required for conjugation are induced by Ste11 and diploids are formed,
the resulting expression of both mating-type alleles inactivates Pat1 (Ran1)
kinase, causing hypophosphorylation and further activation of Ste11
(Kitamura et al., 2001
;
Matsuyama et al., 2000
;
McLeod et al., 2000
).
Hypophosphorylated Ste11 is not required for expression of pheromone-response
genes, but it is required for expression of early meiotic genes such as
mei2+ and may further activate transcription of its own
gene (Yamamoto, 1996
). Thus,
ste11+has an additional layer of regulation not necessary
for IME1; it sequentially activates first conjugation genes and then
meiotic genes.
Regulation of IME2 signal integration at the URS1
site
IME2 is also regulated by several distinct signals, but these
signals are integrated at a single regulatory element, the upstream repression
site 1 (URS1) (Fig. 1B). URS1
is bound by the Ume6p transcription factor under all conditions tested. When
IME2 is repressed, Ume6p is bound to the Sin3p-Rpd3p complex. The
transition from IME2 in this state to actively expressed
IME2 involves two steps
(Washburn and Esposito,
2001). First, the Sin3p-Rpd3p complex is inactivated and may
dissociate from Ume6p. Second, Ume6p associates with Ime1p; Ime1p contains a
transcriptional activation domain and causes the transcription of
IME2 (Bowdish et al.,
1995
; Rubin-Bejerano et al.,
1996
). The stability of this Ume6p-Ime1p complex determines
whether IME2 is transcribed and is regulated by both starvation (G1
arrest) and glucose. Starvation (by nitrogen limitation) activates Rim11p, a
Gsk3 family kinase (Xiao and Mitchell,
2000
). Rim11p phosphorylates both Ime1p and Ume6p, and this
phosphorylation stabilizes the Ume6p-Ime1p association
(Malathi et al., 1997
;
Malathi et al., 1999
). In
contrast, glucose destabilizes the Ume6p-Ime1p complex by repressing
expression of Rim15p, a third kinase required (through an unknown mechanism)
for Ume6p-Ime1p association (Vidan and
Mitchell, 1997
). Thus both nutritional signals converge to
regulate IME2 transcription by modulating the stability of the same
transcription factor complex.
The cohort of genes expressed during meiotic initiation
After IME1 induction, a tightly coordinated transcriptional
program ensues. Microarray analysis reveals that approximately 300 genes are
induced at least three-fold during meiosis, and this entire program of meiosis
can be conveniently grouped into seven sequential waves of expression
(Chu et al., 1998;
Primig et al., 2000
). Members
of a group of coexpressed meiotic genes often share common regulatory sites
and are regulated by common transcription factors (reviewed in
Vershon and Pierce, 2000
).
For example, in addition to IME2, many other early meiotic genes
contain a URS1, and several of these genes require IME1 for
activation for example HOP1 and SPO13.
Hop1p is required for pairing of homologous chromosomes, and Spo13p prevents
the separation of sister chromatids in the first meiotic division
(Lee et al., 2002
;
Shonn et al., 2002
;
Woltering et al., 2000
).
One way that genes are co-regulated is by a concerted change in the
chromatin structure at their promoters. For example, the Ume6p-Sin3p-Rpd3p
complex described above (Fig.
1B) represses transcription because Rpd3p deacetylates histones at
these promoters (Kadosh and Struhl,
1997; Kadosh and Struhl,
1998
; Rundlett et al.,
1998
). Rpd3p can be recruited to promoters that do not contain
URS1 by other transcription factors
(Kurdistani et al., 2002
).
Deacetylation of promoter nucleosomes by Rpd3p prevents association of the
SAGA complex with these promoters (Deckert
and Struhl, 2002
). SAGA contains a histone acetylase, Gcn5p, and
indeed as cells initiate meiosis the IME2 promoter becomes associated
with this enzyme (Burgess et al.,
1999
).
Ume6p also recruits the Isw2p repressor complex to the promoter of
IME2 and many other genes (Fazzio
et al., 2001; Goldmark et al.,
2000
). This complex, which is related to the Swi/Snf family of
ATP-dependent chromatin-remodeling enzymes, represses genes by repositioning
the promoter nucleosomes into transcriptionally inactive chromatin
(Kent et al., 2001
;
Langst and Becker, 2001
). The
Isw2p complex contributes to repression of IME2 and other early
meiotic genes during growth and also to their induction under sporulation
conditions and hence is required for meiotic initiation
(Trachtulcova et al., 2000
).
Thus, the Isw2p complex, Rpd3p complex, and Gcn5p complex may coordinately
regulate many early meiotic genes through a concerted switch in the chromatin
structure of these promoters. Two other complexes that remodel chromatin, the
RSC (Nps1p-Sth1p) and the Set3 complex, also affect regulation of
IME2 and other early meiotic genes
(Pijnappel et al., 2001
;
Yukawa et al., 1999
).
Interlocked regulation of genes expressed at different times in
meiosis
Even when IME1 is overexpressed from a plasmid, IME2
transcription still requires G1 arrest and is still repressed by glucose. This
result is consistent with IME2 transcription depending on both Ime1p
expression and additional nutritional signals that regulate the Ume6p-Ime1p
complex. As described below, there are at least two other types of regulation
of IME1 and IME2.
IME2 repression of IME1
Expression of Ime2p leads to the eventual repression of IME1
transcription during late stages of meiosis
(Shefer-Vaida et al., 1995;
Smith and Mitchell, 1989
).
More directly, Ime2p kinase may phosphorylate Ime1p and target it for
degradation (Guttmann-Raviv et al.,
2002
). These two negative-feedback loops on IME1
expression ensure that Ime1p is expressed in a narrow window relative to
Ime2p. The more extended expression of Ime2p is consistent with other results
indicating that Ime2p has a continued role during the progression of meiosis
(Foiani et al., 1996
;
Sia and Mitchell, 1995
).
Taken together, these results suggest that after IME2 is initially
induced by Ime1p, further IME2 expression does not require Ime1p
during later stages of meiosis.
Feedback repression of IME1 by replication blocks
Meiotic DNA replication is among the first cellular events to occur after
IME1 and IME2 are induced, and efficient replication during
meiosis is dependent on expression of both genes
(Foiani et al., 1996).
Interestingly, the reverse may also be true. That is, continued expression of
IME2 may depend on efficient progression through meiotic DNA
replication, because when replication is blocked by hydroxyurea, the
association of Ume6p and Ime1p is inhibited, and IME2 transcription
is repressed (Lamb and Mitchell,
2001
). This result suggests that a checkpoint function is induced
when replication is blocked that prevents continued initiation of meiosis.
Targets of IME2
Like Ime1p, Ime2p has multiple targets. One such target is Sic1p, an
inhibitor of the Clb-Cdc28 kinases (Dirick
et al., 1998; Stuart and
Wittenberg, 1998
). Phosphorylation of Sic1p by Ime2p kinase
targets Sic1p for degradation, thus activating Clb-Cdc28p. Clb-Cdc28p kinase
induces meiotic DNA replication; thus activation of Ime2p kinase directly
induces meiotic DNA replication. During the mitotic cell cycle, Sic1p is
phosphorylated by Cln-Cdc28p kinase rather than Ime2p, and phosphorylation at
multiple sites on Sic1p is required for Sic1p degradation
(Nash et al., 2001a
).
Possibly, the fact that Ime2p rather than Cln-Cdc28p targets Sic1p for
degradation in meiosis explains why initiation of replication is delayed in
meiosis relative to its timing in the cell cycle.
A second target for Ime2p is NDT80, which encodes a transcription
factor that induces genes expressed during middle stages of meiosis
(Chu and Herskowitz, 1998;
Hepworth et al., 1998
). The
NDT80 promoter, in addition to containing two URS1s, also contains
two middle sporulation elements (MSEs). Ime1p bound to the NDT80 URS1
only partially activates NDT80 transcription when Sum1p, a repressor
protein, is bound to MSE (Xie et al.,
1999
). Ime2p kinase eliminates Sum1p repression at the MSE through
an unknown mechanism (Pak and Segall,
2002
), and at the same time phosphorylates Ndt80p
(Sopko et al., 2002
). Once
phosphorylated, Ndt80p can bind to MSE to fully induce expression of its own
gene and other genes that bear a MSE. For example, Ndt80p is required for
transcription of CLB2 in meiosis
(Sopko et al., 2002
).
CLB2 contains an MSE and encodes the B-type cyclin that triggers
meiotic chromosome segregation. Thus Ime2p, which is expressed early in
meiosis, causes expression of the Ndt80p transcription factor, and Ndt80p then
induces genes expressed in middle stages of meiosis. Indeed, IME2
contains an MSE site, which may allow its expression even after IME1
is repressed.
Possible targets of nutritional controls after meiosis has
initiated
After meiosis initiates, progression of the meiotic program depends, in
part, on expression of IME1 and IME2 and, in part, on
continued nutritional signals. Indeed, when IME1 is overexpressed
from a plasmid, the early meiotic events, such as meiotic replication and
recombination, occur efficiently even in the absence of a non-fermentable
carbon source (Lee and Honigberg,
1996). In contrast, the late meiotic events, such as the meiotic
divisions and spore formation, do not occur. These results imply that there
are nutritional controls on later meiotic processes that are independent of
the nutritional controls on IME1 and IME2. Independent
nutritional controls on late meiotic genes may explain why cells in early
stages of meiosis are able to abort the meiosis and `return to growth' when
transferred from sporulation conditions to growth conditions. It will be
interesting to determine whether critical regulators of middle meiotic gene
expression such as Ndt80p and Sum1p are regulated by nutrients separately from
the nutritional controls on IME1 and IME2.
In summary, two general features of nutritional regulation of early meiotic genes have emerged over the past few years. First, nutritional signals independently control transcription of several different target genes, for example IME1, IME2 and possibly NDT80. Second, expression of each target gene is tightly coordinated with expression of other target genes and with cellular events. The presence of both independent and interlocking controls on key meiotic regulators such as IME1, IME2 and NDT80 may provide fail-safe mechanisms to ensure that meiotic initiation only occurs under appropriate conditions. In addition, these controls allow cells to continually respond to a changing environment.
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Signal transduction pathways that mediate nutritional controls on meiotic initiation |
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Activation of meiosis by starvation/G1 arrest
S. cerevisiae arrest in G1 in response to starvation
(Werner-Washburne et al.,
1993), but it is not understood how the absence of any single
essential nutrient causes the starvation response. Whatever the mechanism of
G1 arrest, cells must arrest before they can initiate meiosis
(Hirschberg and Simchen,
1977
). As a result, many mutants that affect the timing of G1
arrest will also affect the timing of meiotic initiation. In fact, even
auxotrophic markers, such as ura3 and leu2, can affect the
timing of meiotic initiation. For this reason, the timing of meiotic
initiation should only be compared in strains containing exactly the same
auxotrophies (Purnapatre et al.,
2002
).
CLN expression
Many of the signaling pathways that regulate entry into G1 arrest converge
to regulate expression of CLN3, which encodes a G1 cyclin
(Belli et al., 2001;
Cherkasova et al., 1999
;
Jenkins and Hannun, 2001
;
Nash et al., 2001b
). Cln3p is
present at constant levels during the cell cycle, but functions primarily to
promote the transition from G1 to S phase. When G1 arrest occurs, Cln3p levels
decline rapidly (Gallego et al.,
1997
; Parviz and Heideman,
1998
). This decline is also required for meiotic initiation
because CLN3 inhibits IME1 expression and Ime1p localization
to the nucleus (Colomina et al.,
1999
). During G1 phase, Cln3p activates the Swi4p-Swi6p complex
(also called SBF), which is required for expression of two other G1 cyclins,
CLN1 and CLN2 (Levine et
al., 1996
). SWI6 and CLN2 (but not
CLN1) are required for repression of IME1, although the
mechanism for this repression is not known
(Purnapatre et al., 2002
).
Nitrogen starvation
It is often stated that initiation of meiosis in S. cerevisiae
requires starvation for nitrogen, but it is not certain if nitrogen directly
represses meiotic initiation or if nitrogen starvation promotes meiosis
indirectly by causing G1 arrest. Some evidence favors the latter hypothesis,
because meiosis is not blocked by the presence of nitrogen when other
essential nutrients are limiting (Freese
et al., 1982; Freese et al.,
1984
). On the other hand, several nitrogen-sensing pathways affect
the timing of entry into meiosis. Both of the pathways described below, the
TOR2 signaling pathway and the UPR pathway, illustrate the
difficulty in distinguishing between direct and indirect roles of nitrogen in
regulating entry into meiosis.
The TOR2 pathway modulates several nutritional signaling pathways
including the nitrogen discrimination pathway (reviewed in
Raught et al., 2001). This
pathway is activated when the nutritional environment of the cell contains
only poor nitrogen sources. The Tor2p pathway can be activated by the drug
rapamycin, and this activation allows meiosis and sporulation under growth
conditions. However, microarray analysis indicates that activation of the
Tor2p pathway by rapamycin does not directly induce sporulation genes; instead
the Tor2p pathway directly controls a number of metabolic genes required for
growth arrest (Hardwick et al.,
1999
). Thus it is likely that the Tor2p pathway stimulates meiosis
by causing changes in metabolism that result in G1 arrest.
Another pathway that senses nitrogen concentration and may be involved in
the switch from the cell division cycle to meiosis involves HAC1.
When nitrogen is present at high concentrations, HAC1 RNA is spliced,
and only this form can be translated
(Schroder et al., 2000).
HAC1 is required to induce the unfolded protein response (UPR)
(Patil and Walter, 2001
) and
may also regulate entry into meiosis. A hac1
mutant induces
IME2 more rapidly than the wildtype, and overexpression of spliced
HAC1 (HAC1i) delays expression of this gene. The
mechanism of IME2 repression by Hac1p is not known, but HAC1
is spliced in non-fermentable carbon sources at higher levels than in glucose
(Kuhn et al., 2001
). Thus
nitrogen could repress initiation of meiosis during growth in non-fermentable
carbon sources in part by promoting HAC1 splicing
(Schroder et al., 2000
).
Activation of meiosis by non-fermentable carbon sources
IME1 transcription requires respiratory metabolism of a
non-fermentable carbon source. When IME1 is overexpressed from a
plasmid, the requirement for respiration to initiate meiosis is bypassed.
Respiration leads to the production of CO2 and hence causes
alkalization of the medium. This alkalization may contribute to meiotic
initiation (Ohkuni and Yamashita,
2000). For example Rim101p is required both for adaptation to
extracellular alkalization (Lamb et al.,
2001
) and for IME1 transcription
(Su and Mitchell, 1993
). In
addition, alkalization of the medium may also activate the Srb10p-Srb11p
cyclin-kinase complex (also called Ume3p-Ume5p and Ssn3p-Ssn8p), and this
activation is required for efficient induction of IME2 transcription
and initiation of meiosis (Cooper and
Strich, 2002
; Ohkuni and
Yamashita, 2000
). Thus respiration may promote both IME1
and IME2 expression by causing alkalization of the medium.
Repression of meiosis by glucose
Even a relatively low concentration of glucose (0.2-0.5%) inhibits both
IME1 and IME2 transcription. As described below, glucose
probably inhibits meiotic initiation through several different signaling
pathways.
A number of cellular processes that respond to glucose are regulated by the
glucose repression pathway (reviewed in
Johnston and Carlson, 1992).
The central component of this pathway is Snf1p kinase, whose activity is
inhibited by intracellular glucose. In particular, Snf1p kinase is required
for expression of IME1 and IME2
(Honigberg and Lee, 1998
), and
the glucose sensors Rgt2p and Snf3p, which act upstream of SNF1
(Ozcan and Johnston, 1999
),
are required to maintain repression of IME1 during later stages of
growth in glucose medium (K.P., Sarah Piccirillo, Rita Lee and S.M.H.,
unpublished).
Extracellular glucose is also sensed by the G-coupled receptor, Gpr1p
(Lorenz et al., 2000;
Rolland et al., 2000
), which
in turn activates Gpa2p, the alpha subunit of a trimeric G-protein complex
(Harashima and Heitman, 2002
).
This complex, once activated, causes activation of protein kinase A (PKA).
Although the role of Gpa2p in regulating meiotic initiation has not been
established, PKA inhibits both IME1 and IME2 transcription
as well as promoting growth. In addition, Gpa2p binds directly to Ime2p to
repress its kinase activity (Donzeau and
Bandlow, 1999
).
The ortholog of GPA2 in S. pombe is
gpa2+, which also activates PKA. Glucose represses
gluconeogenic genes through this pathway, and nitrogen represses
ste11+ and the sexual cycle through the same pathway
(Higuchi et al., 2002).
Nitrogen starvation specifically activates Stm1, which is homologous to
G-protein-coupled receptors (Chung et al.,
2001
). Once activated, Stm1 binds and inhibits Gpa2, allowing
ste11+ transcription. Thus, although Gpa2 represses
meiotic initiation in both S. cerevisiae and S. pombe, it is
regulated by different signals in the two yeast species.
Glucose transiently activates the Ras pathway under some conditions, and a
more sustained activation of Ras is caused by intracellular acidification
(Thevelein and de Winde,
1999). S. cerevisiae have two RAS genes, and
expression of one of them, RAS1, is induced by glucose. Ras proteins
activate both the Cdc42p/Ste20p MAP kinase pathway and the PKA pathway.
Although both of these pathways control pseudohyphal differentiation
(Mosch et al., 1999
;
Pan and Heitman, 1999
), only
the PKA pathway controls meiotic initiation. In S. pombe, the single
RAS homolog, Ras1, activates rather than represses meiotic
initiation. S. pombe Ras1 does not regulate the PKA pathway, instead
it regulates localization of Byr1 and activation of the Byr1/Byr2/Spk1 MAPK
pathway (Bauman and Albright,
1998
; Ozoe et al.,
2002
). Thus S. cerevisiae Ras proteins activate the PKA
pathway to repress meiotic initiation, whereas S. pombe Ras1
activates the Byr1 MAPK pathway to stimulate meiotic initiation.
The idea that glucose represses meiotic initiation in S.
cerevisiae through multiple pathways is consistent with the finding that
glucose is still able to repress meiosis when either the PKA pathway or the
glucose repression pathway is inactive. For example, glucose represses meiotic
initiation in a cyr1-1 (adenylyl cyclase) mutant even though PKA is
inactive in this mutant (Matsumoto et al.,
1983), and glucose can also represses meiosis effectively in a
gpa2
mutant (Donzeau and
Bandlow, 1999
). Conversely, glucose represses meiotic initiation
in an rgt2
snf3
double mutant (K.P., S.P.,
R.L. and S.M.H., unpublished), even though the glucose repression pathway is
not fully activated in this mutant.
In summary, each signal that regulates meiotic initiation may be transduced through multiple pathways. For example, nitrogen starvation may stimulate meiotic initiation through both the Tor2p pathway and the Hac1p pathway, and, similarly, glucose may repress meiotic initiation through both the glucose repression pathway and the Gpa2p/PKA pathway. Comparisons between signaling networks controlling meiotic initiation in S. cerevisiae and S. pombe suggest that each regulatory network has evolved to adapt to a particular ecological niche. Indeed, the same signaling enzymes (e.g. Ras and Gpa2p) are used to different purposes in the two yeast. It seems likely that as each yeast species adapts to particular environments, existing pathways and signaling components are duplicated or modified to provide a specific signal code for the species.
Crosstalk between signaling pathways in control of meiotic
initiation
Signaling pathways are integrated into networks when the pathways that
transduce these signals converge to regulate the same signal transduction
enzyme. Signaling enzymes regulated by more than one signal can be considered
to act as nodes in the signaling network. In this section, several examples of
this type of integration are discussed.
Integration of glucose and respiratory controls on meiosis
When both glucose and a non-fermentable carbon source are present in the
medium, IME1 expression and initiation of meiosis are completely
repressed. This result can be explained because glucose represses Snf1p kinase
activity, and Snf1p is required for expression of respiratory enzymes
(Ronne, 1995). In addition to
controlling respiration, Snf1p kinase may activate meiotic initiation
directly. For example, initiation of meiosis occurs in the absence of
respiration when IME1 is overexpressed from a plasmid, but even
IME1 overexpression is not sufficient to allow efficient meiotic
initiation in a snf1
mutant
(Honigberg and Lee, 1998
).
Thus Snf1p probably promotes meiotic initiation through other targets besides
respiratory enzymes.
Signal integration within the PKA pathway
As mentioned above, PKA both promotes growth and represses IME1
and IME2 transcription. Because PKA is activated by intracellular
cAMP, adenylyl cyclase (Cyr1p/Cdc35p), the enzyme that generates cAMP, is a
critical regulator of PKA activity. Adenylyl cyclase activity is controlled by
both the Gpa2p pathway (responding to glucose) and the Ras2p pathway
(responding to intracellular acidification and possibly other signals); thus
adenylyl cyclase can be considered to be a signaling node that integrates
these two pathways (Thevelein and de
Winde, 1999).
The PKA pathway contains other components that serve as potential signal
nodes. For example, GPR1 transcription is induced when cells are
starved for amino acids and nitrogen (Xue
et al., 1998). GPR1 encodes the receptor that activates
Gpa2p in response to glucose. A second example is Bcy1p, the regulatory
subunit of PKA. Bcy1p is localized primarily in the nucleus during growth in
glucose but localized throughout the cell during growth in ethanol, and
presumably this localization of PKA controls its activity
(Griffioen et al., 2000
).
PKA targets as sites for signal integration
Several of the targets of the PKA pathway are also regulated by other
signaling pathways, indicating that these targets could serve as signaling
nodes. One example is Rim15p kinase, which promotes the interaction of Ume6p
and Ime1p (see above). Glucose represses RIM15 expression, whereas
PKA directly inhibits the activity of Rim15p by phosphorylating it. Thus
Rim15p represents a signaling node whose expression is controlled by one
pathway and whose activity is regulated by another.
IME1 may be repressed by the PKA pathway through the Msn2p-Msn4p
transcription complex. PKA hyperphosphorylates Msn2p-Msn4p, which inhibits its
function as a transcriptional activator
(Garreau et al., 2000).
Msn2p-Msn4p activates transcription of many stress-response genes by binding
to the stress response element (STRE) present in the promoters of these genes
(Smith et al., 1998
). Some of
these stress-response genes, for example, TPS1 (trehalose phosphate
synthetase), are also required for induction of IME1
(De Silva-Udawatta and Cannon,
2001
). More directly, an STRE is present in the IME1
promoter and may be required for IME1 expression
(Sagee et al., 1998
).
PKA may also regulate the Msn2p-Msn4p complex by phosphorylating Sok2p
(Ward and Garrett, 1994),
which is thought to bind Msn2p-Msn4p and convert it to a transcriptional
repressor (Shenhar and Kassir,
2001
). Independently of the PKA pathway, SOK2 expression
is induced by glucose (Shenhar and
Kassir, 2001
). Thus, Sok2p regulation is similar to Rim15p
regulation. In both cases, PKA regulates the activity of the enzyme, whereas a
different pathway regulates its expression.
There are likely to be other PKA targets in meiosis. In fact, cAMP levels
drop rapidly as cells initiate meiotic differentiation and then rise again
soon after this decrease (Uno et al.,
1990). This fluctuation suggests that PKA represses meiotic
initiation but stimulates other meiotic events. Indeed although adenylyl
cyclase mutants initiate meiosis precociously, they do not progress through
sporulation normally, and they form largely two-spored rather than four-spored
asci (Uno et al., 1990
).
In summary, although the signaling network controlling meiotic initiation is only partially known, several types of node have been revealed. First, the activity of an enzyme can be controlled by more than one pathway or signal. For example, glucose regulates adenylyl cyclase through the Gpa2p pathway whereas intracellular acidification regulates adenylyl cyclase through the Ras2p pathway. Second, one pathway can regulate expression of a gene whereas a second pathway regulates activity of its product. For example, RIM15 is regulated post-translationally by the PKA pathway, but transcriptionally through an independent pathway. Third, the presence of one signal may regulate the transmission of another signal. For example, when glucose inactivates Snf1p kinase, it blocks expression of genes required for respiration.
![]() |
Genomic approaches |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Microarray analysis of genes induced during meiosis has identified a number
of genes that were not previously known to function in meiosis, but were
subsequently determined to play important roles in the meiotic program
(Chu et al., 1998;
Gerton and DeRisi, 2002
;
Rabitsch et al., 2001
;
Smith et al., 2002
;
Valencia et al., 2001
).
Similarly, genomic studies using two-hybrid assays or mass-spectrometric
analysis of protein complexes (Gavin et
al., 2002
; Ho et al.,
2002
; Ito et al.,
2001
; Uetz et al.,
2000
) have identified potential interactions between known meiotic
proteins and proteins without a known meiotic function. Identifying which of
these interactions are biologically relevant is assisted by comparing data
from independent genome-wide interaction studies
(von Mering et al., 2002
) and
correlating protein interaction data with microarray data
(Kemmeren et al., 2002
).
Genomic analysis has been useful for identifying regulatory elements that
are present in meiotic genes. In addition to verifying the presence of URS1 or
MSE elements in a large number of meiotic genes, microarray expression data
has identified other putative regulatory elements shared by genes expressed in
meiosis (Bussemaker et al.,
2001; Pilpel et al.,
2001
). For example, approximately 75% of the metabolic genes
expressed very early in the meiotic program contain at least one of five
different short motifs (Bussemaker et al.,
2001
). Many early meiotic genes also contain an MCB box or both an
MCB and an SCB box in their regulatory region
(Bussemaker et al., 2001
;
Pilpel et al., 2001
). These
regulatory sequences are found in the promoters of genes required for the
transition from G1 to S phase during the cell cycle and hence may also be
important in induction of genes required for DNA replication in meiosis. In
addition to microarray data analysis, an alternative method for identifying
regulatory motifs is to compare the regulatory regions of homologous genes in
closely related species (Cliften et al.,
2001
), and the genomes of several of these `sensu stricto' species
have recently been sequenced. As one example, this `phylogenetic footprinting'
analysis has revealed several regulatory elements in addition to the URS1 in
the promoter of the early meiotic gene, REC102
(Jiao et al., 2002
).
Completion of the sequencing of the yeast genome (Goffeau, 1996) enabled
the creation of a set of mutants that each lack one of approximately 5000
non-essential genes in the genome (Giaever
et al., 2002). Homozygous diploid deletion mutants have been used
in large-scale screening for sporulation-defective mutants
(Briza et al., 2002
;
Enyenihi and Saunders, 2003
).
Interestingly, mutants exhibiting defective autophagy, a process of
large-scale protein degradation, did not undergo either the meiotic divisions
or spore formation. Autophagy may be required in meiosis to salvage nitrogen
and other metabolites used for biosynthesis. Another process that may play a
role in meiotic initiation is RNA processing. Several proteins that affect
IME1 expression are involved in this process: Rim4p is a putative
RNA-binding protein (Soushko and
Mitchell, 2000
; Deng and
Saunders, 2001
), Ime4p is an RNA methyltransferease
(Clancy et al., 2002
), and
Ire1p is an RNA endonuclease involved in regulated splicing
(Schroder et al., 2000
).
![]() |
Conclusion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Our knowledge of the signaling network controlling initiation of meiosis is incomplete, and it is certain that more signaling pathways and more connections between pathways will be discovered. The rapid progress in the field over the past few years can be attributed in part to the synergy created between detailed genetic and biochemical studies on the one hand and genome-wide studies on the other. In the future, as genome data is gathered for more yeast species, comparisons between species may provide an additional way to correlate signal networks with biological function.
The switch between growth and meiosis in yeast provides an opportunity to identify a complete signaling code, a network of signal transduction enzymes that translates different combinations of signals into appropriate cellular responses. One key to identifying such codes will be to determine the involvement (or lack of involvement) of each component of the network in responding to each signal. Identification of such codes in yeast should be help us to decipher the even more complex signaling interactions that occur in higher organisms.
![]() |
Acknowledgments |
---|
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