Department of Ophthalmology and Visual Sciences, Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA
E-mail: edward.levine{at}hci.utah.edu
SUMMARY
Regardless of the species, the development of a multicellular organism requires the precise execution of essential developmental processes including patterning, growth, proliferation and differentiation. The cell cycle, in addition to its role as coordinator of DNA replication and mitosis, is also a coordinator of developmental processes, and is a target of developmental signaling pathways. Perhaps because of its central role during development, the cell cycle mechanism, its regulation and its effects on developing tissues is remarkably complex. It was in this light that the Keystone meeting on the cell cycle and development at Snowbird, Utah in January 2004 was held.
The meeting covered many topics and addressed several crucial questions regarding the cell cycle and development. How is cell number controlled during organogenesis, and what is the relationship between cell size and the cell cycle? How is cell division coordinated during metazoan development of multicellular organisms, and how are developmental cues integrated with the cell cycle? How do cells know when to start and stop dividing? While I attempt to cover these topics here, one message that became clear from this meeting was that the cell cycle, despite its conserved nature, can be modified in diverse and novel ways to adapt to the demands of a growing cell, tissue or embryo (Fig. 1).
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In most proliferating somatic tissues, growth is tightly coupled to the
cell cycle, which makes the increase in cell number a reliable indicator of
tissue growth and size during development. There are several ways in which
cell numbers in a tissue can be modulated. These include alterations in
patterning (which determines the initial size of the stem or founder cell
population), the rate and mode of proliferation of founder and progenitor
cells, cell death and cell migration. In plants, cell proliferation and growth
primarily contribute to organ size; the removal of overproliferated cells and
cell migration does not occur. How do plants coordinate these mechanisms to
produce an organ of the appropriate size and cell number? Keiko Torri
(University of Washington, Seattle, WA, USA) showed that the leucine-rich
receptor-like kinases ERECTA, ERL1 and ERL2 together are crucial for the
normal proliferation of cells that form the above-ground organs in
Arabidopsis. It is not known whether these proteins directly regulate
the cell cycle, but the expression of some cell cycle regulator genes was
reduced in erecta, erl1, erl2 triple mutants. Interestingly, these
mutants had much larger cells than wild-type plants, suggesting that cell
growth compensated to some extent for the reduced proliferation
(Shpak et al., 2004).
In Drosophila, the coordination of cell proliferation and cell
death is essential for determining the correct numbers of cells in a tissue.
Georg Halder's lab (M.D. Anderson Cancer Center, Houston, TX, USA) performed a
genetic screen to find mutants with enlarged tissues. They found that flies
with mutations in hippo, salvador and warts have larger
tissues than normal due to a combination of ectopic proliferation and reduced
cell death (Fig 2A). Warts and
Hippo are kinases, and Salvador is an adaptor protein. These three proteins
form a complex and negatively regulate the G1/S phase cyclin Cyclin E (CycE),
and the anti-apoptotic protein DIAP1 (Drosophila Inhibitor of
Apoptosis Protein 1), to control proliferation and cell death, respectively
(Udan et al., 2003). Halder
suggested that this complex acts to coordinate proliferation and
apoptosis.
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Cell growth is tightly coupled to cell cycle progression. However, how this
coupling occurs is not clear, and several speakers presented diverse models
that addressed this question. Bruce Edgar (Fred Hutchinson Cancer Center,
Seattle, WA, USA) discussed how cell growth in polyploid tissues of the
Drosophila larvae is tightly coupled to nutritional availability. His
lab has previously shown that overexpression of the insulin receptor, other
insulin pathway components, or the transcription factor Dmyc (Dm - FlyBase),
drives cell growth in larval tissues
(Britton et al., 2002;
Saucedo et al., 2003
;
Pierce et al., 2004
). However,
although the insulin pathway acts as a nutrient sensor, the effects on cell
growth by Dmyc are not dependent on nutrient availability or the insulin
pathway, indicating that Dmyc drives cell growth by an independent mechanism.
Furthermore, they found that Dmyc selectively promotes the expression of genes
involved with protein synthesis and RNA transcription
(Orian et al., 2003
). Another
question raised by Edgar was, how do growth regulators like Dmyc and the
insulin pathway promote endocycles (a modified cell cycle associated with
increased cell size in which growth and DNA replication are uncoupled from
mitosis, resulting in polyploidy; Fig.
1, and see below)? Edgar proposed a relatively simple oscillatory
mechanism, in which CycE levels accumulate in phase with DNA replication and
dE2F (E2f - FlyBase) activity increases out of phase with DNA replication, and
these two proteins regulate each other through feedback mechanisms. Growth
cues such as the insulin pathway and Dmyc feed into this oscillation by
increasing the levels of CycE protein, thereby promoting the G to S phase
transition in endocycling tissues (Edgar
and Orr-Weaver, 2001
).
Martin Raff (University College, London, UK) addressed how cell growth and
proliferation are coordinated in mitotic mammalian cells, and specifically
whether mammalian cells have cell-size checkpoints that are analogous to those
in yeast (checkpoints arrest the cell cycle if proper cell-cycle events are
not completed). Experiments in which the cell-cycle and growth rate of rat
Schwann cells were modulated in culture by extracellular factors indicate that
these cells may not have such checkpoints
(Conlon and Raff, 2003).
Instead, cell size at cell division appears to depend on how fast the cells
progress through the cell cycle and how fast they grow, which in turn depends
on extracellular signals that control cell cycle progression, cell growth, or
both. By contrast, Jim Umen (Salk Institute, La Jolla, CA, USA) has found
that, in the unicellular green alga Chlamydomonas reinhardtii, the
activity of the retinoblastoma-like protein Mat3/Rb is sensitive to a minimum
cell size and acts as a sensor of size threshold. Cells grow during their gap
(G) phases of the cell cycle, and in Chlamydomonas, the G1 phase
varies in length; cells can grow to be very large and of varying size.
Following the initial entry into S phase, the cell then goes through multiple
rounds of S to M (S-M) cycles, termed fission cycles
(Fig. 1), during which all
daughters ultimately attain a uniform size. The coupling of cell size to the
number of fission cycles depends on Mat3/Rb activity
(Umen and Goodenough, 2001
),
which might (1) prevent premature entry into fission cycles and (2) restrict
the number of fission cycles according to cell size. Interestingly, Umen
described how this mechanism of cell size regulation is coupled to
developmental programming in multicellular relatives of
Chlamydomonas, like Volvox carteri, and how Volvox
may use the Mat3/Rb pathway to regulate asymmetric cell division and germ/soma
differentiation.
Early embryonic cell cycles
Metazoans undergo a period of rapid cell cycles, termed cleavage cycles,
immediately following fertilization (Fig.
1). In Drosophila, these divisions produce the syncitial
blastoderm and in Xenopus, the blastula, but these cycles are
remarkably similar in these two species in that the size or mass of the embryo
does not increase compared with the fertilized eggs from which they arise. In
each case, the cell cycles are similar in design; they have S-M oscillations
without intervening gap phases and they function independently of
transcription. In Drosophila, the early cleavage cycles (cycles 2-9)
are remarkably fast; they take approximately 8.5-9 minutes and S phase
possibly lasts 3.5 minutes. How then, is the entire genome replicated in
this short time? This is an especially important question because, during S
phase, heterochromatin replicates later than euchromatin, and the entire
genome must be precisely and completely duplicated during each cycle. Does
heterochromatin exist during the early cleavage cycles? According to Patrick
O'Farrell (UC San Francisco, CA, USA), heterochromatin is present but its
replication is not delayed, suggesting that DNA replication through
heterochromatin is regulated differently in cleavage cell cycles compared to
later cell cycles. O'Farrell suggested that zygotic gene products are
responsible for the appearance of late-replicating heterochromatic DNA and the
lengthening of S-phase, because its later replication does not occur until the
maternal-zygotic transition (MZT).
Another important question regarding the Drosophila cleavage
cycles is how the activity of the mitotic cyclin and cyclin-dependent kinase
(CDK) complex, CycB/Cdk1, is regulated to promote mitosis. High CycB/Cdk1
activity prevents DNA re-replication and promotes entry into the mitotic
program, and low CycB/Cdk1 activity causes cells to exit mitosis. This
typically occurs via the anaphase promoting complex (APC)-dependent
degradation of CycB. During the cleavage cycles, however, CycB/Cdk1 activity
does not oscillate, except for highly localized Cdk1 inactivation due to CycB
degradation at mitotic spindles in late metaphase; this appears to be
sufficient for mitotic exit during these cycles
(Huang and Raff, 1999;
Su et al., 1998
). Are high
CycB levels the default during the cleavage cycles? Evidence suggests that
high CycB levels are actively regulated prior to the MZT by proteins encoded
by pan gu (png), plutonium (plu) and
giant nuclei (gnu). png putatively encodes a
serine/threonine kinase, and forms a complex with PLU and GNU that is required
for kinase activity, as discussed by Terri Orr-Weaver (MIT, Cambridge, MA,
USA). However, she also showed that CycB is not a direct substrate of this
kinase, so work is under way to identify substrates that regulate CycB
(Lee et al., 2003
).
The cell cycle and the switch from maternal to zygotic control
The MZT in Drosophila and the mid-blastula transition (MBT) in
Xenopus are both characterized by a shift in developmental control
from maternally provided proteins to those produced by the embryo. This shift
also coincides with a switch from cleavage cycles to cell cycles that have gap
phases, which is partly due to an acquired dependence on the nascent
transcription of cell cycle genes, including histones. Prior to the MZT in
Drosophila, histone mRNA is maternally supplied, but once zygotic
transcription begins, histone RNA levels begin to oscillate during the cell
cycle and accumulate to high levels only in S-phase, when DNA synthesis
occurs. In cell cycles that have a G1 phase, histone transcription is
upregulated at the G1/S boundary and depends on CycE/Cdk2 activity. However,
in Drosophila, the cell cycles immediately following the MZT (cycles
14-16) have a G2 phase, but lack a G1 phase
(Fig. 1). What then triggers
the synthesis of histone RNA during these cycles? Bob Duronio (University of
North Carolina, Chapel Hill, NC, USA) described certain components of this
regulation. He showed that zygotic histone transcription depends on the G2
phosphatase Stringcdc25a, which is limiting in these cycles, and
that new histone mRNA synthesis occurs after the histone mRNA from the
previous S-phase is degraded. Furthermore, the oscillation in histone mRNA
levels during different phases of the cell cycle depends on blocking
polyadenylation, which is mediated by Stem Loop Binding Protein (SLBP) binding
to a stem-loop in the 3' untranslated region (UTR) of histone mRNA. In
slbp mutants, histone mRNAs are inappropriately polyadenylated at the
MZT, resulting in the aberrant accumulation and loss of their cell cycle
oscillation (Lanzotti et al.,
2002; Sullivan et al.,
2001
). Similarly, in Xenopus, a change in the regulation
of adenylation of maternal cell cycle transcripts occurs at the MBT. Rebecca
Hartley (University of New Mexico, Albequerque, NM, USA) showed that the
deadenylation of CycA1 and CycB2 mRNA is required for the
timed downregulation of CycA1 and B2 proteins, which is necessary for the
slowing of S phase and introduction of the G2 phase
(Audic et al., 2001
). As in
Drosophila, this deadenylation depends on RNA-binding proteins
interacting with the 3' UTRs of the cyclin transcripts.
Patterning and morphogenesis
In addition to cell cycle regulation at the MZT/MBT, patterning and
morphogenesis may be directly regulated by cell-cycle-related events at the
MBT, although in distinct ways. Daniel Fisher (CNRS, Montpellier, France)
described his work with Marcel Mechali. This work shows that progression
through a limited number of cell cycles at the MBT in Xenopus are
necessary and sufficient for HoxB gene cluster activation in the neurectoderm,
an important step in anterior-posterior (AP) patterning, and that more cell
cycles are required for the correct spatial expression of HoxB genes along the
AP axis. Further experiments in mammalian cells suggest that DNA replication
through the HoxB locus may be a prerequisite for spatially regulated gene
activation (Fisher and Mechali,
2003). In contrast to Fischer's work, which exemplifies the
importance of how promoting cell cycle activity influences patterning, Paul
Mueller (University of Chicago, IL, USA) described how restricting cell cycle
activity influences morphogenesis. Following the MBT, the Xenopus
embryo undergoes convergent extension, during which the cell cycle arrests
transiently in the paraxial mesoderm. Preventing this block disrupts the
positioning and segmentation of the paraxial mesoderm and convergent extension
for reasons unknown. However, Mueller showed that this cell cycle arrest
requires the G2 kinase Wee2, a zygotically transcribed gene that is activated
at the MBT and expressed in the paraxial mesoderm. Morpholino knockdown of
Wee2 expression levels relieved the cell cycle block and disrupted convergent
extension (Leise and Mueller,
2004
).
Switching from mitotic cell cycles to endocycles
Mechanisms have evolved to ensure that the entire genome is replicated once and precisely each mitotic cell cycle to maintain genomic stability. However, endocycles can also occur (Fig. 1), which have alternating G to S phases (G-S), thus these cycles do not cause an increase in cell number. Endocycles are important for cell growth and for several developmental processes in plants and animals, and as such considerable attention is being given to understanding their regulation. As may be expected, endocycles use the cell cycle machinery to block mitosis.
One model system being used to study endocycle regulation is the
Drosophila oocyte cyst. The cyst consists of 16 clonally related
cells, the oocyte and 15 nurse cells, which are cytoplasmically coupled to
each other by ring canals. By stage 9, the oocyte is arrested in prophase of
Meiosis I, but the nurse cells are highly polyploid due to endocycles.
Enveloping the cyst are follicle cells, which have several important
functions, including establishing dorsoventral (DV) polarity. Once enough
follicle cells are produced by cell division, they undergo endocycles during
formation of the oocyte cyst. Two important questions raised at the meeting
were: (1) how does the oocyte stay arrested in meiosis while the nurse cells
undergo endocycles, especially considering their cytoplasmic linkage; and (2)
how does the mitotic-to-endocycle transition occur in the follicle cells? Mary
Lilly (NIH, Bethesda, MD, USA) addressed the first question by presenting
evidence that expression levels of the CKI Dacapo (Dap) are highly locally
regulated within the cyst (Fig.
3A). High levels of Dap in the oocyte block CycE/Cdk2 activity and
low levels of Dap around the nurse cell nuclei activates CycE/Cdk2, allowing
nurse cells to progress into S phase (Hong
et al., 2003). Hannele Ruhola-Baker (University of Washington,
Seattle, WA, USA) addressed the second question and showed that Notch
signaling is required for the transition from mitotic cycles to endocycles
(Fig. 3A). They found that in
response to Notch, Dap and Stringcdc25a expression is repressed and
Fizzy-related (FzrCdh1) expression is promoted
(Shcherbata et al., 2004
). One
model is that Notch activity coordinates the regulation of important
checkpoints during this transition: FzrCdh1 promotes APC activity
by keeping CDK activity low, which is important for progression through early
G1; low levels of Dap allows the transition from G1 to S by raising CycE/Cdk2
activity; and low Stringcdc25a blocks mitosis by keeping CycB/Cdk1
activity low.
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Consistent with the role of FzrCdh1 in plant endocycles, Yukiko Mizukami (UC Berkeley, CA, USA) overexpressed FzrCdh1 in Arabidopsis to alter the timing of transition from mitotic cycles to endocycles in the leaf epidermal lineage to study the relationship of cell fate and patterning, and cell cycle regulation. Interestingly, modifying the timing of endocycle transition caused changes in patterning but not cell fate within the leaf epidermis. Mizukami suggested that endocycles do not drive differentiation per se, but rather are necessary for the correct patterning of the leaf epidermis.
Exiting the cell cycle
Once metazoan embryos begin organogenesis, most somatic cells are
undergoing the prototypical mitotic cell cycle
(Fig. 1). In these somatic cell
cycles, the G1 phase provides an opportunity for external inputs to influence
the autonomous mechanisms of the cell cycle. This is an especially critical
phase for most developing tissues, as it is often when cell cycle exit is
coordinated with terminal differentiation. This has been a strong focus of
investigation in the vertebrate central nervous system (CNS), and Martine
Roussel (St. Jude Children's Research Hospital, Memphis, TN, USA) described
how areas of the brain utilize combinations of two CKI classes, the Ink4 and
Cip/Kip proteins, to initiate cell cycle exit at the onset of neuronal
differentiation and to maintain neurons in a postmitotic state. Roussel and
Neil Segil showed that p19Ink4d loss in the mouse induces deafness
due to inappropriate cell cycle re-entry in differentiated, sensory hair
cells, which is followed by apoptosis (Fig.
2B) (Chen et al.,
2003). Roussel also demonstrated that many CNS neurons require
both p19Ink4d and p27Kip1 to maintain cell cycle exit in
their differentiated state (Cunningham et
al., 2002
; Zindy et al.,
1999
). In p19Ink4d and
p27Kip1 double knockout mice, postmitotic, differentiated
neurons re-entered the cell cycle in many parts of the brain and retina
(Fig. 2C), a phenotype not
observed in the single knockouts. These findings indicate that the cell cycle
arrest normally maintained in terminally differentiated cells is dependent on
CKI activity beyond the initial event of cell cycle exit.
How CKIs are regulated to promote cell cycle arrest is a question with no
single answer. Examples abound that suggest that CKIs are regulated at many
levels, from transcription to post-translational modification. Two distinct
examples were described at the meeting by Joan Seoane (Sloan Kettering, New
York, NY, USA) and Ludger Hengst (Max Planck Institute, Martinsreid, Germany).
Seoane described work with Joan Massague in which TGFß-induced cell cycle
arrest depends not on TGFß-dependent SMAD transcription factors, but
rather on the direct interactions of SMAD proteins with other transcription
factors, such as FOXO (Seoane et al.,
2004), ATF3 (Kang et al.,
2003
) and E2F4/5 (Chen et al.,
2002
), which are downstream of signals other than TGFß. This
indicates that the cell cycle arrest mediated through the CKIs that are the
transcriptional targets of TGFß (such as p21Cip1) is probably
due to combined extracellular inputs. Hengst showed that the RNA-binding Hu
proteins regulate the translational efficiency of p27Kip1.
p27Kip1 contains a small open reading frame (µORF) at the
extreme 5' end of the mRNA and an internal ribosome entry site (IRES)
between the µORF and the p27Kip1 ORF. The HuR protein binds in
the IRES region and may interfere with the access of the IRES to ribosomes,
thereby reducing the translational efficiency of the p27Kip1 ORF
(Gopfert et al., 2003
;
Kullmann et al., 2002
). As HuR
is expressed in proliferating cells, this mode of p27Kip1
regulation explains how p27Kip1 protein levels might be kept in
check in proliferating cells that express high levels of p27Kip1
mRNA.
G1 regulators in development: critical...or not?
Surprisingly, several labs have found that many cell cycle components
predicted to be essential for cell cycle regulation in embryonic mouse tissues
are largely dispensable during development. Knockouts of D-cyclins, E-cyclins,
Cdk2, Cdk4 and all G1 regulators do not directly or globally disrupt
embryogenesis. For example, Peter Sicinski (Dana Farber Cancer Institute,
Boston, MA, USA) pointed out that many embryonic tissues still developed
fairly well when D-cyclins were not detected in mice with double knockout
combinations (Ciemerych et al.,
2002), and Philip Kaldis (NIH, Bethesda, MD, USA) showed that in
the absence of Cdk2, mice are viable but sterile due to a requirement for Cdk2
in both the male and female germlines
(Berthet et al., 2003
;
Ortega et al., 2003
). Although
the lack of global phenotypes resulting from knockouts of these essential cell
cycle regulators could be explained by the compensatory actions of other
proteins, these studies suggest that the embryonic somatic cell cycle has a
high degree of plasticity that is more sophisticated than simple redundancy.
An important goal is to identify how the cell cycle adapts in the absence of
these key proteins.
One approach that may help reveal how cell proliferation continues in the
absence of central G1 regulators is to sensitize cells by removing multiple
cell cycle proteins. In Drosophila and C. elegans, genetic
screens are being done in sensitized backgrounds (viable strains or tissues
that harbor mutations in G1 regulators) to find novel regulators of G1
progression. In Drosophila, CycE is required for proliferation in the
imaginal eye disc, and Helena Richardson's group (MacCallum Cancer Institute,
Melbourne, Australia) used a CycE hypomorph to screen for dominant suppressors
of this phenotype (Brumby et al.,
2002). New genes identified from this screen included the cell
polarity genes discs large and scribble. scribble mutant
clones had increased CycE expression and extra proliferation compared with the
adjacent tissue, but did not overgrow because of compensatory cell death
(Brumby and Richardson, 2003
).
Interestingly, scribble's role in cell proliferation may be linked to
the downregulation of the Hedgehog (Hh) pathway. Consistent with this, Wei Du
(University of Chicago, IL, USA) showed that Hh signaling directly stimulates
CycE expression (Duman-Scheel et al.,
2002
). Sander van den Huevel (MGH, Charlestown, MA, USA) and David
Fay (University of Wyoming, Laramie, WY, USA) also described screens to
identify novel regulators of G1 progression in C. elegans. One
advantage of studying this in C. elegans is that its stereotypic
pattern of cell division and differentiation should allow subtle developmental
phenotypes to be detected. This formed the basis for genetic identification of
parallel acting genes and for genes that act in the temporal control of cell
division, several of which regulate levels of the CKI Cki-1.
Concluding remarks
These were just some of the excellent talks that were presented at the meeting. While many of the talks reveal just how versatile the cell cycle can be during different developmental events, it is also clear that we have much more to learn about the basic workings of the cell cycle within the context of developing tissues, and how it is that the cell cycle can be modified to fit into a developmental program, and yet can be so adaptable as to function `normally' in the absence of supposed key components. Fortunately, these questions will not, and should not, be answered in isolation because this meeting revealed just how much common ground exists between the diverse model systems being investigated. In many ways, this meeting launched the study of cell cycle and development as a global, rather than as an organism-specific, field.
ACKNOWLEDGMENTS
I wish to thank the speakers who were kind enough to answer my inquiries, and I also apologize to those whose work I was unable to highlight.
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