BBAGRM-00799; No. of pages: 5; 4C:
Biochimica et Biophysica Acta xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
journal homepage: www.elsevier.com/locate/bbagrm
Stress-mediated tuning of developmental robustness and plasticity
in flies☆
M. Elgart 1, O. Snir 1, Y. Soen ⁎,1
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
a r t i c l e
i n f o
Article history:
Received 18 June 2014
Received in revised form 31 July 2014
Accepted 2 August 2014
Available online xxxx
Keywords:
Stress
De-canalization
Developmental robustness and plasticity
Epigenetics
Non-Mendelian inheritance
Adaptation
a b s t r a c t
Organisms have to be sufficiently robust to environmental and genetic perturbations, yet plastic enough to cope
with stressful scenarios to which they are not fully adapted. How this apparent conflict between robustness and
plasticity is resolved at the cellular and whole organism levels is not clear. Here we review and discuss evidence
in flies suggesting that the environment can modulate the balance between robustness and plasticity. The outcomes of this modulation can vary from mild sensitizations that are hardly noticeable, to overt qualitative changes in phenotype. The effects could be at both the cellular and whole organism levels and can include cellular de-/
trans-differentiation (‘Cellular reprogramming’) and gross disfigurements such as homeotic transformations
(‘Tissue/whole organism reprogramming’). When the stress is mild enough, plastic changes in some processes
may prevent drastic changes in more robust traits such as cell identity and tissue integrity. However, when the
stress is sufficiently severe, this buffering may no longer be able to prevent such overt changes, and the resulting
phenotypic variability could be subjected to selection and might assist survival at the population level. This article
is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
© 2014 Elsevier B.V. All rights reserved.
1. The interplay between developmental robustness and plasticity
The development of a multi-cellular organism is an extremely complicated morphogenetic process mediated by stage-dependent interactions between differentiating cells. Its ability to generate reproducible
outcomes under a wide range of environmental and genetic perturbations is indicative of remarkable developmental robustness (or canalization [1–4]). This robustness is necessary for maintaining evolved
patterns of development that are critical for survival and reproduction.
Excessive robustness, however, could compromise the ability of cells
and the entire organism to cope with novel or rare stressful conditions.
These conditions could reflect unusual combinations of stable changes
either in the external environment or in internal ingredients (e.g. genetic and epigenetic changes in some of the cells). In some of these stressful
scenarios, robustness of specific phenotypes could become maladaptive
thus adding to the stress. Maintaining such maladapted phenotypes can
be detrimental, especially when the stressful event persists for a long
duration. In these cases, it may be advantageous to lower stability
and increase developmental plasticity (viewed as responsiveness to external and internal environments [5]). This may assist in coping with a
severe stress during the lifetime of a given individual [6–8] and could
☆ This article is part of a Special Issue entitled: Stress as a fundamental theme in cell
plasticity.
⁎ Corresponding author.
E-mail address: [email protected] (Y. Soen).
1
Tel.: +972 8 9346011; fax: +972 8 9344118.
contribute to the survival of the entire population by increasing interindividual variability. Thus, a developing organism needs to be sufficiently stable yet flexible. How this tension between developmental robustness and plasticity is resolved at the mechanistic level is a longstanding question in gene regulation [9–13], particularly with respect
to scenarios involving new stressful conditions (as opposed to frequently encountered types of stress, such as heat shock and starvation, for
which a response program has been previously established during
evolution) [14,15].
One possible (though not exclusive) way of achieving satisfactory
degrees of robustness and plasticity is to modulate the balance between
stability and flexibility based on the type and extent of stress. In particular, severe stressful conditions can compromise the robustness of the
developmental process, thereby tilting the balance toward reduced stability and increased variability. Conversely, conditions involving much
milder stress are less disruptive, thus favoring higher stability. Such
context-dependent regulation of the balance between stability and flexibility can be achieved by environmental interference with the canalizing function of systems that normally assist in preventing phenotypic
and genotypic variation. Although canalization likely results from collective action of many processes [16,17], previous work has indicated
specific mechanisms conferring particularly notable canalizing activities. These include buffering of genetic variability by the Hsp90 chaperone [18–22], epigenetic buffering by Polycomb [23,24], stabilizing
negative feedback by microRNAs [25–28], and piwi-mediated silencing
of transposon activity [29,30] or of existing variation [29]. Stressmediated disruption of these (and likely many other mechanisms) can
http://dx.doi.org/10.1016/j.bbagrm.2014.08.004
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Please cite this article as: M. Elgart, et al., Stress-mediated tuning of developmental robustness and plasticity in flies, Biochim. Biophys. Acta
(2014), http://dx.doi.org/10.1016/j.bbagrm.2014.08.004
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M. Elgart et al. / Biochimica et Biophysica Acta xxx (2014) xxx–xxx
alleviate cellular and/or organismal resistance to phenotypic/epigenetic
changes, thereby increasing the flexibility of the organism and the range
of phenotypic outcomes [31].
De-canalization can occur at the cellular and/or whole organism
levels. Additionally, the extent and type of change can vary substantially
depending on the exact details of the perturbing event (e.g. type and
strength of the stress, the affected cells and tissues, and the stage in
development). For example, a decanalization event can result in
mild sensitization which impacts particular traits only in conjunction
with an additional disturbance. In other cases, decanalization could
result in ectopic expression of transcription factors capable of inducing a different cell fate program thus leading to cellular de- and/or
trans-differentiation ('cellular reprogramming'). Proliferation and migration of such reprogrammed cells can alter tissue identity and organization, an outcome that could be viewed as 'reprogramming' at the
tissue and/or whole organism level. Notably, the outcomes are not necessarily restricted to the normal repertoire of cell types and tissue organizations and can result in abnormal cellular/tissue states,
tumorigenesis [32,33], and/or gross disfigurements of the organism.
All these outcomes are potentially realizable in the ‘epigenetic landscape’ [34] of genetically defined organisms, but are typically prevented
by the combined action of canalizing mechanisms which often confine
the process of development to the characteristic, stage-dependent patterns [31]. Some of these canalizing mechanisms also contribute to the
integrity of the genome itself (e.g. DNA repair mechanisms and transposon silencing systems). Disruption of such canalizing activities can
therefore interfere with phenotypic as well as genetic outcomes.
2. Examples of induced decanalization in flies
Environmentally-induced decanalization has largely been underexplored because of the much more common interest in mechanistic
understanding of the ‘normal developmental program’ (as opposed to
deviations from the program). Nonetheless, a number of studies in
flies have begun to provide evidence supporting the abovementioned
context-dependent function of canalizing systems:
2.1. Environmental induction of homeotic transformations (ether-induced
bithorax phenocopy)
Perhaps the most striking examples of decanalization are those
involving dysregulation of Hox genes, thus leading to homeotic transformations. Under normal conditions, these transformations are
prevented by epigenetic memory systems which prevent aberrant expression of hox genes, and in particular by the activity of Polycomb
group (PcG) and Trithorax group genes (trxG) [35–39]. Following initial
hox genes-mediated specifications of segments, their identities are
maintained by Polycomb and trithorax gene complexes. Drosophila
Polycomb genes maintain repressed state of hox (and other gene) targets by methylating histones affecting chromatin structure (particularly
trimethylation of histone H3-lysine 27, H3K27me3 [40]). Trithorax on
the other hand, promotes maintenance of active expression by methylating histone H3-lysine 4, H3K4 [41]. PcG and trxG targets are defined
by Polycomb/Trithorax response elements (PRE/TREs) which recruit
the PcG and trxG proteins, via a platform of sequence specific DNA binding proteins [42]. Under large numbers of environmental and genetic
perturbations, these mechanisms are preventing cellular and tissue
transformations by suppressing dysregulation of hox (and other)
genes. However, this prevention is not unlimited. Indeed, brief (10–
20 min) exposure of fly embryos to vapor of dimethyl ether within a
particular time window (2 to 4 h after egg deposition) has been
shown to promote a homeotic transformation resembling the mutant
phenotypes of the bithorax hox gene complex (BX-C) [43–46]. This
transformation anteriorizes the third thoracic segment, resulting in a
range of deformations in haltere tissue (with or without abnormalities
in additional tissues). In pronounced cases, the transformation is
manifested by an extra pair of wings instead of halteres [43,44,46–48].
Wings and halteres are both generated from primordial larval organs
named “imaginal discs”, each originating from a particular embryonic
body segment. The identity of each segment is specified during early
embryonic development by hox genes of the Antennapedia and the
Bithorax gene clusters [49]. In particular, the Ultrabithorax gene, Ubx
[50], specifies the axial identities of cells in the third thoracic segment
and is required for the development of the haltere during normal ontogeny. Accordingly, loss of Ubx function results in transformation of haltere identities toward wing fates [39,51,52] and its ectopic expression
in the developing wing promotes inverse transformation toward haltere
[39,53]. The phenotypic similarity between genetic loss of Ubx function
and the response to ether vapor suggests that the exposure downregulates Ubx in the haltere [50]. This might reflect interference with
the trithorax-mediated maintenance of Ubx expression. Indirect evidence for this scenario was provided by increased homeotic responsiveness to ether in trx heterozygous flies [54], indicating that reduction in
trithorax function enhanced the environmental disruption of morphogenetic integrity of the flies. In this case, however, the suppression of
trithorax was achieved by genetic means and it has not yet been
shown that exposure to ether compromises trithorax function.
2.2. Decanalization by suppression of Hsp90
Another remarkable example of an environmentally-regulated
decanalization has been given by stress-induced suppression of Hsp90
[18], a chaperone that keeps many unstable signal transducers and developmental regulators poised for activation [55,56]. The first demonstration in flies [18], showed that mutations in Hsp90, or alternatively,
its suppression by geldanamycin lead to a variety of developmental abnormalities, including transformations of tissue organization. The alterations are likely mediated by multiple activities, including uncovering of
existing genetic variability [18], disruption of the normal function of
non-mutant targets [29,57], and unleashing of transposons [30]. This
demonstrated an explicit molecular mechanism which contributes to
the stability of developmental patterns and whose suppression by stress
increases phenotypic variability.
The penetrance and expressivity of abnormalities in Hsp90-deficient
flies could be further increased by elevating the temperature and can
become independent of Hsp90 deficiency following several generations
of selection of aberrant flies [18]. This enhancement over generations
has been proposed to reflect enrichment of genetic alleles which increase the sensitivity to express the phenotype, and has been termed
genetic assimilation [58,59]. Interestingly, however, similar accumulation was observed also in an isogenic line of flies, iso-KIlf − 1, carrying
a Kruppel (Kr) mutation which sensitizes for ectopic outgrowth protruding from the ventral region of the eye [57]. This outgrowth appears
to be related to Hsp90 and trithorax because the phenotypic impact of
KIlf − 1 in wild type flies is small, but greatly enhanced by maternal deficiencies in Hsp90 and in various chromatin regulators, including genes
of the trithorax group (particularly verthandi, vtd). Remarkably, inhibition of Hsp90 by exposure to geldanamycin only in one generation, and
subsequent selection of abnormal flies for multiple generations increased the penetrance of this phenotype toward a plateau which
persisted even in the 13th generation. This accumulation in an isogenic
line shows that assimilation of an environmentally-induced transformative event does not necessarily require initial polymorphic background or successive exposures to the initial trigger [57].
Altogether, these studies suggest that the various intact functions of
Hsp90 buffer against environmental and genetic perturbations. This
provides a potential mechanism for accumulating genetic mutations
which might be detrimental under frequently encountered conditions
but may be beneficial under severe stress. The evidence connecting
Hsp90 with trithorax [57,60] and piwi functions [29] further supports
the systemic nature of canalization, and provides examples for potential
Please cite this article as: M. Elgart, et al., Stress-mediated tuning of developmental robustness and plasticity in flies, Biochim. Biophys. Acta
(2014), http://dx.doi.org/10.1016/j.bbagrm.2014.08.004
M. Elgart et al. / Biochimica et Biophysica Acta xxx (2014) xxx–xxx
mechanisms by which external stress (or mutations in the transuding
pathway) could interfere with epigenetic memory of cell identity.
2.3. Decanalization by suppression of Polycomb and heterochromatin
Induced decanalization can also be mediated by environmental suppression of the Polycomb system, as demonstrated in two different
models of stress: Injury in prothoracic leg discs [23] and exposure to
toxic stress in arbitrarily determined tissues of developing larvae [24].
The injury model is based on the removal of a leg disc from the mid
third-instar larvae, chopping off (fragmenting) about 1/4 of this disc,
and cultivating the remaining part in the abdomen of 1 d old female
flies. Cultivation of the fragmented (but not the intact) disc triggered a
regenerative response accompanied by cellular transdetermination
from a leg to wing fate [23]. The transformed cells were restricted to
the regenerating fragmented region. Similar transformation can be induced by exposure to the wingless (wg) morphogen in ectopic domains
[61]. This response to wg is enhanced on the background of Polycomb
heterozygotes, suggesting that Polycomb function might be reduced in
the fragmented discs. In an elegant set of experiments [23], the Paro
lab has shown that the fragmentation induced the Jun N-terminal kinase (JNK) wound healing response and that activation of this signaling
pathway suppressed the Polycomb function in JNK-induced cells. Using
a reporter for Polycomb-mediated silencing, they further showed that
the cellular transdetermination events were localized to those cells in
which the Polycomb function was suppressed. Additionally, analysis of
injury on the background of genetic reduction in JNK function alleviated
the suppression of Polycomb and reduced the transdetermination response [23]. Since transdetermination entails qualitative deviation
from the usually robust (canalized) cell identity, this work provided
substantial evidence in support of decanalization mediated by environmental suppression of a usually canalizing system (Polycomb).
A conceptually similar scenario was demonstrated while studying
how flies cope with rare settings of stress, in which they are lacking a
suitable regulatory program [24]. This model was based on the following synthetic drug/anti-drug setup: larvae are exposed, via their feed,
to a toxic concentration of G418 antibiotic that is lethal to wild type
flies (which are not equipped with an endogenous resistance gene
against G418). To provide the larvae with a potential to cope, the flies
were engineered to express a resistance gene (neoGFP) downstream a
specific developmental promoter. This led to expression of the resistance gene only in restricted tissues which do not fully overlap with
all the tissues that were exposed to G418. This setup leads to toxic stress
in tissues that are exposed to G418 but do not express the resistance
gene. In essence, the larvae are given a potential solution (i.e. a rescue
gene), but they are lacking a pre-evolved regulatory program required
for expressing this gene in the relevant tissues. This could potentially
allow evaluation of the ability of inherent flexibility to support deviations from the ‘developmental program’, and to study whether (and
how) this flexibility could contribute to survival prior to the emergence
of a new adaptive program. To assess the generality of outcomes, the
stress was applied to different lines of transgenic larvae, each carrying
the resistance gene downstream of a different developmental promoter.
Exposure to G418 revealed a clear tendency to expand the domain of
expression of the resistance gene in a promoter-specific manner (expansion was noticed in over 50% of the promoter cases without a single
promoter case in which the domain of expression was narrowed). This
bias toward ectopic activation of developmental promoters suggested
that the stress is compromising Polycomb function, which under
milder, frequently encountered conditions assists in preventing
aberrant activation. This was consistent with down-regulation of several Polycomb group genes in the foregut of G418-exposed versus nonexposed larvae. Genetic reduction of Polycomb gene dosage (using mutant alleles of PcG genes or by RNAi against these genes) phenocopied
the tissue-specific inductions of the resistance gene without exposing
the larvae to G418. Conversely, increasing Polycomb function (by an
3
extra copy of Polycomb under the regulation of a heat shock promoter
or by a mutation in a key JNK gene) suppressed the induction of the resistance gene and compromised survival under G418 exposure. As in
the injury model, this demonstrated that environmental disruption of
a usually canalizing agent (Polycomb system) leads to decanalization
manifested by induced expression of developmental genes in ectopic
domains. The increased potential for expressing developmental genes
in the cells can be viewed as de-differentiation of these cells. This
view was also supported in a more explicit experiment in which
reprogramming of differentiated mammalian cells was enhanced by
Utx, a de-methylase which inverses Polycomb function by removing
Polycomb-mediated H3K27 trimethylation [62].
Beyond this environmental regulation of the balance between robustness and plasticity, the larval toxicity model revealed that some of
the stress-induced phenotypes persist for several generations of nonexposed offspring, demonstrating transgenerational implications of
stress-induced decanalization [24]. This includes non-Mendelian inheritance of ectopic activation of developmental promoters. A recent
follow-up study further showed that the parental exposure to G418
modifies the composition of maternal RNA deposited in the early offspring embryo. The modifications include reduction in the maternal
transcript levels of the Polycomb (Pc) gene in early embryos of exposed
parents compared to embryos of non-exposed parents. Analysis of genetically normal offspring embryos of Pc mutant females revealed that
reduction in maternal Polycomb dosage increases the induction of the resistance gene in the non-exposed offspring [63]. This implicated environmental suppression of Polycomb not only in initial decanalization but
also in the inheritance of some of the impacts.
Another remarkable example of heritable decanalization was given
by disruption of heterochromatin state mediated by stress-induced
phosphorylation of dATF-2 [64]. Heterochromatin loci are enriched
with methylation of histone H3 lysine-9 (H3K9) and with binding of
heterochromatin protein 1 (HP1), which can promote epigenetic gene
silencing. ATF-2 is a transcription factor contributing to heterochromatin nucleation [65] and has a transactivation domain that can be phosphorylated by stress-activated protein kinases (SAPKs), such as p38
[66,67]. Under non-stressful conditions, dATF-2 is thought to assist epigenetic silencing by forming a heterochromatin-like structure. In this
context, dATF-2 is a canalizing agent contributing to the integrity of heterochromatin silencing. However, under exposure to heat shock or osmotic stress, dATF-2 is phosphorylated by the p38 kinase, Mekk1,
resulting in disruption of the heterochromatin-like structure and derepression of the respective loci [64]. dATF-2 therefore appears to provide another example of the same concept in which the balance between stability and variability is regulated by stress-induced inhibition
of a canalizing agent. As in the case of Polycomb suppression [24],
stress-induced decanalization by phosphorylation of dATF-2 generated
phenotypes that were inherited over multiple generations. Moreover,
the phenotypic outcome was shown to increase over successive generation of stress [64].
2.4. Decanalization by microRNAs
Despite the dramatic effects and the obvious relevance of Hsp90 and
chromatin regulators to the maintenance of cell identity and tissue integrity, it is important to realize that the stability of development is supported by a variety of additional processes and mechanisms. One
example is provided by microRNAs which can post-transcriptionally
regulate the expression of many genes and have been proposed to confer robustness to programs of gene expression [26]. The canalizing effect
of microRNAs in flies was demonstrated by the influence of the miR-7
microRNA on the stability of gene expression and organ specifications
[27]. Drosophila miR-7 participates in regulating the determination of
photoreceptor cells and sensory (proprioceptor and olfactory) organ
precursor, SOP cells. Photoreceptor determination is regulated by a
network-like architecture involving miR-7 and the transcriptional
Please cite this article as: M. Elgart, et al., Stress-mediated tuning of developmental robustness and plasticity in flies, Biochim. Biophys. Acta
(2014), http://dx.doi.org/10.1016/j.bbagrm.2014.08.004
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repressor Yan, required to maintain photoreceptor precursors in an undifferentiated state [68]. Determination of sensory organ precursor
(SOP) cells is regulated by another network involving miR-7 and the
transcriptional activator atonal (ato), which induces genes enabling a
subset of proneural cluster (PNC) cells to adopt a sensory organ precursor (SOP) fate [69].
In photoreceptor precursor cells, Yan represses miR-7 transcription
directly and indirectly through Ttk69 (‘coherent feed-forward loop’
[70]). In a second loop, the transcription of yan is repressed by Pnt-P1
both directly and indirectly via Pnt-P1 mediated induction of miR-7
(which in turn represses Yan). It has been suggested that these coherent
feed-forward loop structures confer stability against fluctuations [27]. In
sensory organ precursor (SOP) cells, Ato directly activates transcription
of E(spl) [71,72], but indirectly represses it by inducing miR-7, which in
turn represses E(spl). In addition, E(spl) is a direct repressor of ato. Persistent increase of Ato is thought to result in sustained repression of
E(spl) by miR-7, thereby promoting persistent expression of Ato [27].
In either precursor model, miR-7 is predicted to reduce changes in Yan
and Ato expression, thus helping to stabilize the respective cell fates.
This has indeed been shown by analyzing the impact of temperature
steps (between 18 and 30 °C) in wild type versus miR-7 mutant line
[27]. Notably, the phenotypic sensitivity to the loss-of-function mutation in miR-7 was larger under this temperature challenge compared
with unchallenged flies.
These findings indicate that miR-7 assists in protecting cell fate determination within a certain range of environmental fluctuations.
Whether or not this buffering activity of miR-7 is itself regulated by
the environment is not known. However, as indicated for the other canalizing agents, it is plausible that other forms (or severities) of stress
could compromise the expression and/or function of miR-7 thus reducing its buffering function and increasing developmental flexibility.
mimics of such scenarios were provided by synthetic gene recruitments
in yeast which created novel stress in an otherwise regular external environment [14,73]. Although the novel stress in these examples was artificially engineered, analogous scenarios can be induced by naturally
occurring changes. Owing to the many possibilities for such changes
within each cell of a given multi-cellular organism, and the large
number of potentially affected cells, the prevalence of new stressful
conditions could be significantly higher than often imagined. To a presumably large extent, organisms use existing generic mechanisms for
coping with many of these stressful conditions. Some of these capabilities are conferred by efficient systems such as DNA repair, apoptosis, immune surveillance, and other mechanisms capable of addressing a wide
range of newly encountered scenarios. Yet, despite the incredible efficiency and versatility of these systems, they are probably insufficient
to fully prevent or alleviate all these newly encountered scenarios.
This raises a critical need for comprehensive understanding of plastic
responses to novel stress, including: (1) how these responses are activated and coordinated at the cellular and whole organism levels,
(2) whether and how they might become beneficial for the affected individual or for the entire population, (3) what are the implications for
the offspring, and (4) whether and how these responses might be connected to longer-term establishment of new adaptations. How organisms respond to these conditions, is therefore an important open
question, yet to be resolved both at a conceptual and mechanistic level.
3. Future directions
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Acknowledgements
This work was supported by the Sir John Templeton Foundation
(grant ID: #40663) and the Israel Science Foundation (grant No. 1860/
13). YS is Incumbent of the Daniel E. Koshland Sr. Career Development
Chair at the Weizmann Institute.
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Please cite this article as: M. Elgart, et al., Stress-mediated tuning of developmental robustness and plasticity in flies, Biochim. Biophys. Acta
(2014), http://dx.doi.org/10.1016/j.bbagrm.2014.08.004