IUBMB
Life, 61(6): 607–612, June 2009
Critical Review
Understanding the Mechanism of the Dormant Dauer Formation of
C. elegans: From Genetics to Biochemistry
Yunbiao Wang, Anastasia N. Ezemaduka, Yan Tang and Zengyi Chang
National Laboratory of Protein Engineering and Plant Genetic Engineering, School of Life Sciences,
Center for Protein Science, Peking University, Beijing, China
Summary
Dauer is a dormancy state that may occur at the end of developmental stage L1 or L2 of Caenorhabditis elegans when the
environmental conditions are unfavorable (e.g., lack of food,
high temperature, or overcrowding) for further growth. Dauer
is a nonaging duration that does not affect the postdauer adult
lifespan. Major molecular events would include the sensing of
the environmental cues, the transduction of the signals into
the cells, and the subsequent integration of the signals that
result in the corresponding alteration of the metabolism and
morphology of the organism. Genetics approach has been
effectively used in identifying many of the so-called daf genes
involved in dauer formation using C. elegans as the model.
Nevertheless, biochemical studies at the protein and metabolic
level has been lacking behind in understanding this important
life phenomenon. This review focuses on the biochemical
understanding so far achieved on dauer formation and dormancy in general, as well as important issues that need to be
addressed in the future. Ó 2009 IUBMB
IUBMB Life, 61(6): 607–612, 2009
Keywords
Caenorhabditis elegans; dormancy; dauer; metabolism;
DAF proteins; heat shock proteins.
INTRODUCTION
Unlike nonliving matter, living beings have developed various
mechanisms to sense and respond to the fluctuations of environmental conditions, especially when these become highly unfavorable (usually designated as stress conditions). Entering a resting
dormant state will allow some organisms to effectively withstand
the adverse conditions and, thus, has been adopted as a common
Received 7 March 2009; accepted 24 March 2009
Address correspondence to: Chang Zengyi, School of Life Sciences,
Peking University, #5 Yiheyuan Road, Haidian District, Beijjing
100871, China. Tel: 86-10-6275-8822. Fax: 86-10-6275-1526.
E-mail: [email protected]
ISSN 1521-6543 print/ISSN 1521-6551 online
DOI: 10.1002/iub.211
survival strategy by both prokaryotes (e.g., E. coli and M. tuberculosis) and eukaryotes (e.g., yeasts, ciliates, and nematodes).
Many animals have long been noticed to enter an inactive
state, known as hibernation, during the winter when food availability is limited. The fertilized eggs of soil nematode C. elegans would normally develop into their adult and reproductively
mature stage within 3–5 days, after quickly going through the
L1 to L4 larval stages, molting at the end of each stage. Nevertheless, C. elegans is also able to enter a quiescent state, designated as dauer (a German word meaning ‘‘enduring or persisting’’) stage, usually at the end of the L2 (or less commonly of
the L1) larva stage, under harsh conditions such as lack of
food, high-population density, or temperature increase (see Fig.
1) (2, 3). The dauer state allows C. elegans to commonly survive for up to 120 days (instead of the normal 20 days!), as
well as to effectively disperse via phoresy (relationship in which
one organism transports another organism of a different species)
to a more favorable condition place.
The dauer larvae are easily distinguished from other developmental stages by presenting an adverse-resisting and energysaving state: the animals stop taking any food, appear thin and
dense, usually remain motionless, but can remarkably respond
to some stimuli. Also, unfed dauer larvae possess a dauer-specific behavior known as nictation, in which a larva mounts a
projection and stands on its tail, waving its head in the air. The
dauer state is also correlated with a developmental suspension
of the reproductive organs. On returning to favorable living
conditions, the larva exits the dauer state and resumes the normal development process by first entering the L4 larva stage.
Genetic studies have been quite effective in identifying genes
whose mutation either promotes or suppresses the dauer formation. However, biochemical studies to understand how encoded
proteins are actually involved in the dauer formation process
and eventually generate the dramatic morphological and metabolic transformations still remain scarce. This review emphasizes on the progresses achieved so far in understanding the biochemical process of dauer formation.
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Figure 1. The life cycle of C. elegans. Dauer is an alternative
larval stage, taken when the environmental conditions are
unfavorable for further growth. Dauer larvae appear to be nonaging and can live nearly 10 times their normal lifespan (about
20 days). The length of time the animal spends at a certain
stage is indicated.
CELLS SENSING THE ENVIRONMENTAL
HARSH CONDITIONS
Which cells are the initial sensors of living conditions that
will either drive the C. elegans larvae to normal developmental
process or enter the dauer formation program (Fig. 2)? The answer to this question was initially hinted by the observation that
C. elegans mutants unable to form dauer larvae were simultaneously defective in their sensory functions, with the morphology
of the ciliated neurons being affected in quite a few of these defective mutants (4). This was subsequently confirmed by Laser
ablation studies, where it was observed that the amputation of
ciliated amphid neurons, particularly the ADF, ASG, ASI, and
ASJ, induced the animal development into dauer larvae, regardless of environmental conditions (5). The observation above
suggests that these neurons will instigate the development of
larvae into adult stages under favorable conditions. Nevertheless, such positive roles will be annihilated by the unfavorable
environmental cues and result in the formation of dauer larvae.
WHAT MOLECULES SIGNAL A HIGH POPULATION
DENSITY OF C. Elegans?
It has been reported that communication on the aspects of
mate selection to population density between individuals of the
same animal species occurs via the action of pheromones
excreted into the surroundings (6, 7). Pheromones in C. elegans
were originally detected as potent male attractants produced and
Figure 2. Schematic illustration of the likely major events driving C. elegans to go through a normal developmental process or
to enter the dormant dauer state.
excreted by the hermaphrodites. Pheromones signaling a high
density of C. elegans population were later identified and characterized as small molecules containing both fatty acids and
sugar moieties, which increase the frequency of dauer larva formation (8, 9).
Although their chemical nature and physiological function in
promoting dauer formation have been largely documented, the
action of such ‘‘crowding’’ pheromones in promoting the dauer
formation process is still unknown. Unanswered questions
include: what are the targeted sites of the pheromones? Where
are such targets located in the cells? What signaling pathway is
involved? What metabolic processes are affected as a result of
this signaling process? How the signaling of such pheromones
will drive the dramatic morphological and metabolic readjustments seen during dauer larvae formation?
The small size and hydrophobic nature of such pheromones
might allow them to enter the cells. As a matter of fact, targets
to which they bind do not have to be located on the cell surface. Another very interesting question is whether such small
molecules truly function as an active ‘‘pheromone’’ signal, or
they are simply some passive cues excreted by the C. elegans
individuals. Systematic biochemical studies will be appropriate
resolving these pending issues.
WHAT ARE THE KEY GENES AND PROTEINS
INVOLVED IN CONTROLLING THE DAUER
FORMATION PROCESS?
As the formation of dauer larvae in C. elegans is a phenotype easy to observe, a large number of mutant C. elegans have
been generated and screened for a change of this phenotype,
resulting either in a ‘‘constitutive’’ or a ‘‘defective’’ formation
of dauer larvae. About 40 daf (dauer larvae formation) genes
have been identified by selecting mutants of C. elegans that ei-
MECHANISM OF THE DORMANT DAUER FORMATION OF C. elegans
609
Table 1
Proteins encoded by genes associated with the dauer formation
Products of daf-genes
DAF-1, DAF-4
DAF-2
DAF-3, DAF-8, DAF 14
DAF-5
DAF-6
DAF-7
DAF-9
DAF-10
DAF-11
DAF-12
DAF-16
DAF-18
DAF-19, DAF-24
DAF-21
DAF-22
DAF-23 (Age-1)
DAF-28
DAF-36
Assumed function
References
TGF-beta receptor
Insulin receptor
SMAD (cell signaling mediators)
Transcription coregulator (Ski homolog)
Patched-related protein
Development regulatory growth factor TGF-b
Steroid hydroxylase P450
Intraflagellar transport-particle
Guanylyl cyclase
Nuclear hormone receptor
FOXO transcription factor
Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN homolog)
RFX family of transcription factors
Heat shock protein 90 (Hsp 90)
Dauer pheromone regulators
Phosphatidylinositol-3-OH kinase catalytic subunit
Homolog INS-4 and INS-6
Rieske-like oxygenase
12, 13
14
15, 16
17
18
19
20, 21
22
23
24
25, 26
27
28
23
8, 29
30
31
32
Products of DAF-25, DAF-26, DAF-27, DAF-29, DAF-30, DAF-32, DAF-33, and DAF-34 have not been characterized (33).
ther do not produce dauer larvae even when they are starved, or
do so when food is abundantly supplied (10, 11). Many of the
daf genes have been characterized, with the possible biological
functions for their encoded protein products, hinted by analyzing whether they are homologous to proteins of known functions and in turn further biochemical studies when feasible, as
shown in Table 1.
As expected, the majority of these daf genes were later
revealed to function in the cell signaling processes, particularly
in the neuron cells (Table 1). The biochemical nature of about
one fifth of these genetically identified daf genes, meaning the
structure and function of the proteins they encoded, are still
largely unknown (Table 1). Undoubtedly, not all important
genes, involved in the dauer formation process, can be identified
by the genetic approach. Tedious biochemical studies are
needed to unveil the actual function of many of the identified
daf genes, as well as to find out other factors that play key roles
in the formation of a dormant dauer.
As an interesting contrast, similar genetic studies to identify
C. elegans genes that might be important for the aging process
(i.e., by selecting for mutants having an increased life span)
ended with a much shorter list of age genes (34). This implicates that specific lifespan genes are extremely rare, age genes
are essential, or lifespan is controlled in a polygenic fashion. A
more reasonable explanation might be that, unlike dauer formation, the phenotype of aging is difficult to define, thus, greatly
decreases the effectiveness of such traditional genetic studies.
One interesting revelation is that among these ‘‘lifespan’’
genes, one that was later designated as age-1 (35) was found to
be the same as daf-23, encoding a homolog of the p110 catalytic subunit of phosphoinositide 3-kinases (PI3K) and might be
involved in generating the signaling molecule phosphatidylinositol 3,4,5-triphosphate (PIP3) at the plasma membrane (30).
Other daf genes, such as daf-2 and daf-16, were also found to
play key roles in determining the lifespan of C. elegans (14,
36). These revelations strengthened the idea that entering the
dormant state is a way for living organisms to extend their lifespan.
Clearly, knowing that many of the daf genes encode products
of various signaling pathways is far from enough in understanding the molecular events of dauer formation. It is essential to
elucidate what actually occurs in both upstream and downstream events, which are well characterized and highly conserved signaling pathways. It is conceivable that these upstream
and downstream events would dramatically differ in different
cells and organisms. In case of the dauer formation in C. elegans, for example, processes leading to the remarkable morphological alterations (e.g., formation of the thick cuticles and the
sealing of the openings of the digestive system, etc.) would
have to be understood in molecular terms. To get there, there is
no short cut, biochemical studies will be indispensable.
WHAT ROLES DO THE HEAT SHOCK (STRESS)
PROTEINS PLAY IN DAUER FORMATION?
Heat shock proteins (also called stress proteins), a family of
proteins that function to protect living organisms under unfavorable environmental conditions (37), would presumably play cer-
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WANG ET AL.
tain important roles during the formation of the stress-resistant
dauer state of C. elegans. This has been demonstrated by a few
interesting reports as described latter.
The importance of elevated temperature in inducing the formation of the dauer state was nicely demonstrated by an accidental observation of C. elegans entering the dauer stage, growing at 27 8C (3). This was not noticed before because it was
taken as a common practice to shift the temperature from 15 to
25 8C for such high-temperature treatment of C. elegans. This
observation strongly suggests that certain responsive proteins
(including member of the heat shock protein families) pl ay
critical roles in switching the development program to the formation of the dauer state.
As a matter of fact, a high accumulation of Hsp90 mRNA
was detected during the dauer stage, and sharply declined
within 1 h into the recovery stage (38, 39). Additional supporting evidence comes from the report, which revealed that the
most highly expressed transcript in C. elegans dauer larvae was
the small heat shock protein Hsp12.6 (40). As noted earlier, the
importance of Hsp90 was indeed demonstrated in the first mutational studies, where the gene encoding Hsp90 was identified as
daf-21 without knowing its nature (10, 11, 23).
The involvement of the small heat shock proteins in organisms entering the dormant state has also been suggested by
numerous other observations. The small heat shock protein p26
was found to be the most abundant protein (occupying roughly
15% of the total nonyolk embryo protein) in the encysted
embryo stage of Artemia franciscana (41). Similarly, in Mycobacterium tuberculosis, the 16-kDa sHsp was found to exist at a
high level and apparently participated in the formation of a
thickened cell envelope of the dormant bacilli (42). These
observations suggest that the small heat shock proteins play a
role in forming the thickened barrier surrounding the dormant
organism. Therefore, it will be interesting to find out whether
the small heat shock protein Hsp12.6, whose mRNA transcript
was characterized as the most highly expressed in C. elegans
dauer larvae (40), is localized in the thickened cuticle.
Heat shock proteins often possess a structure that is highly
responsive to alterations of the environmental conditions, thus
being ideal to function as effective sensors and effectors for
environmental fluctuations in making the decisions on how to
respond, including the entry, maintenance, and exit of the dormant state for C. elegans. The environmental fluctuation is a
kind of extrinsic noise to the living system, and it is conceivable that signals representing the adverse nature of the surroundings (e.g., heat shock) will have to reach a certain threshold before the decision on entering the dormant state is made.
In other words, environmental fluctuations below a certain
threshold would not switch on the dormancy program. To accomplish such roles, the heat shock proteins may simply alter
their three-dimensional structure or oligomeric status (i.e., quaternary structure), which can occur immediately on the appearance of the stressful conditions (43–45). In contrast, changing
the protein expression profile might take longer responding
time and would lead to a long-term adaptation to the environmental conditions.
ENTERING THE DAUER STATE WOULD REQUIRE A
PROFOUND METABOLIC READJUSTMENT
Dauer larvae do not feed but are able to usually live for as
long as 4 months, depending solely on its internal food reserves.
It is obvious to speculate that the metabolic level would have to
be significantly lowered to allow the dauer larvae to survive
longer than their normal adult lifespan. This hypothesis was initially tested in a trial comparing enzyme levels involved in the
central metabolic pathways of energy production between the
dauer larva and the adult C. elegans (46). The results revealed
an increased rate of glycolysis, gluconeogenesis, and glyoxylate
cycle, but a decreased rate of glycogen biosynthesis, citric acid
cycle, beta-oxidation, and oxidative phosphorylation. These biochemical observations were supported by later analysis of the
transcript profiles (47–49) and 31P-NMR studies (50). Such
NMR studies also revealed that the phosphate mainly exists as
inorganic, instead of the organic high-energy phosphate form in
the dauer state (50), suggesting a low level of ATP in the dormant forms.
Another important aspect of metabolism for C. elegans dauer
larvae would concern the rate of protein synthesis and degradation. Dauer state formation occurs under nutrient starvation conditions, which have been commonly observed to activate the
cellular autophagy pathway allowing the breakdown of the nonvital components and the release of nutrients to ensure the continuation of the vital processes in cells (51). Studies mainly
using RNAi techniques demonstrated that the function of a few
autophagy genes is indeed essential for dauer formation in C.
elegans (52). It would be interesting to find out whether the
overall rate of protein synthesis is decreased in the C. elegans
dauer larvae as predicted.
To get a full picture of the metabolic state and its regulation
mechanism of the dormant organisms, the newly designed proteomic and metabolomic techniques might be effectively and
powerfully applied. Proteomics study may help to reveal the
profile differences of protein types and even the post-translational modifications for the alternative forms of the organism.
Similarly, metabolomic technologies may help to unveil the
major metabolic alterations by characterizing the full composition of small metabolites in the dormant dauer and the normal
larval state. It is envisioned that a combination of proteomics
and metabolomics technologies will provide a systematic characterization on the molecular events related to dormancy.
PROSPECT
Biochemistry seeks to understand the unit of life at the molecular level, despite the diversity in appearance. Although dormancy might be considered as a common strategy for all living
organisms to adapt and resist harsh environmental conditions,
MECHANISM OF THE DORMANT DAUER FORMATION OF C. elegans
its exact way of manifestation seems to vary, occurring at different developmental stages, from fertilized egg (or seeds in
plants) to the adult stage (53). As a result, these phenomena
have been described using different terms: persister in bacteria,
sporulation in yeast, encystment in ciliates, dauer in nematodes,
diapause in insects, hibernation in higher animals, dormancy in
plants, etc. The molecular mechanisms for all these various life
forms to enter, maintain, and exit their dormant status, probably
share more or less common biochemical components. A combination of biochemical and genetic approaches, respectively, focusing more on protein action and metabolic features, and on
genes and phenotype changes, will be, not only highly solicited,
but also extremely powerful in achieving a full understanding
of dormancy phenomena. These phenomena are not only closely
related to the aging ones, but also to those of sleep (54). Lethargies of C. elegans, a quiescent state occurring before each of
the four moults during the larval stage of development, were
suggested to be sleep-like (55). Future studies may demonstrate
a relationship between these two processes and, in turn, suggest
an evolutionary interconnection between them.
Understanding the molecular mechanism of the dormancy
phenomena will also contribute greatly to the treatment of
human diseases caused by infectious pathogens, whose entry
into a dormant state will effectively prevent the action of any
drugs (56). In the same token, cancer cells entering the dormant
state will also resist action of any drugs (57). If ways can be
designed to ‘‘wake up’’ such dormant pathogen or cancer cells,
many related diseases would be treated in a much more effective manner.
ACKNOWLEDGEMENTS
This work was supported by National Natural Science Foundation of China (numbers: 30711120582, 30670022) and the
National Key Basic Research Foundation of China (numbers:
2006CB806508, 2006CB910304).
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