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Centre de Recherche en Reproduction Animale, Facultéde Médecine Vétérinaire, Université de Montréal, 3200 rue Sicotte, St-Hyacinthe, Quebec, Canada J2S7C6
Correspondence should be addressed to B D Murphy; Email: bruce.d.murphy{at}umontreal.ca
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Abstract |
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 Top Abstract IntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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Introduction |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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Recent comprehensive syntheses of literature have appeared on the evolutionary aspects of diapause (Thom et al. 2004), and on the maintenance and termination of diapause (Renfree & Shaw 2000). The molecular regulation of implantation from the uterine perspective has recently been discussed in depth (Dey et al. 2004). In this presentation we address the characteristics of the embryo in diapause and focus on the mechanisms of regulation of this phenomenon, including the environmental and metabolic stimuli that induce and terminate this condition, the hormonal regulatory pathways, and the phenomenon of cell cycle arrest and reactivation.
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The embryo in diapause |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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Two variations on the theme of diapause |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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). Facultative diapause, best known in rodents and marsupials, is the developmental arrest induced by environmental conditions related to the survival of the dam and her ability to nourish developing embryos. Facultative diapause can be produced experimentally in rodents by ovariectomy of the female soon after fertilization, followed by progesterone treatment (Paria et al. 2002). In contrast, obligate diapause is present during every gestation of a species, and is believed to be a mechanism for synchrony of parturition with environmental conditions favorable to neonatal survival. While common in mustelid carnivores, it is also found in the roe deer and some bats (Sandell 1990). In some species, there is seasonal diapause superimposed on diapause resulting from metabolic factors or lactation (Renfree & Shaw 2000).
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Regulation of diapause by external factors |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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Photoperiod and temperature
Reduced ambient temperature is one of the principal factors inducing diapause in invertebrates (Kostal et al. 2000). Low temperature will induce diapause in some reptiles (Shanbhag et al. 2003). In mammals, the role of temperature is best known in the regulation of delayed development in bats (Mead 1993). There is, nonetheless, evidence that elevated temperature induces facultative diapause in rodents (Marois 1982), and that low temperatures can prolong obligate diapause in some carnivores (Canivenc & Bonnin 1979). The physiological mechanisms in mammals are currently unknown.
It was recognized early that photoperiod played an important role in termination of diapause and the consequent induction of implantation (Pearson & Enders 1944). In mustelids, diapause is terminated during lengthening photoperiod, and the lengthening of days prior to and after the vernal equinox influences the timing of implantation in numerous species, including the spotted skunk (Mead 1971) and the mink (Murphy & James 1974). In the seal family, implantation occurs under a regime of decreasing day length (Atkinson 1997). Day length – or, more precisely, a regime of photoperiod in which mink are exposed to light during a critical period from 12 to 16 h after dawn – provides a facultative signal that induces implantation (Murphy & James 1974). Studies in both mink and skunks indicate that the requirement for long days is not absolute, as implantation occurs in animals maintained in constant dark as well as in blinded animals (Mead 1993). The pineal gland was first implicated in studies in which its denervation by cervical sympathetic ganglionectomy disrupted photoperiodic regulation of the termination of diapause (Murphy & James 1974), later confirmed by pinealectomy and melatonin replacement (Bonnefond et al. 1990). While chronic melatonin treatment of mink does not interfere with puberty, ovulation or blastocyst formation in mink, it prevents termination of diapause and implantation (Murphy et al. 1990). Implantation can be rescued by exogenous prolactin in this species, suggesting a single mechanism for photoperiod induction of implantation.
In some macropod marsupials, seasonal regulation of diapause is superimposed on lactational diapause, and long days associated with the summer solstice are the cue that reinitiates embryo development (Renfree & Shaw 2000). Diapause can be terminated by denervation of the pineal in marsupials, implicating melatonin as the effector (Renfree et al. 1981). The environmental cues and their translation into physiological events are less well studied and more difficult to discern in species such as the roe deer, where diapause is terminated during short days (Sempere et al. 1992) or, as in the case of the ursids, when implantation occurs during hibernation (Harlow & Beck 2002).
Metabolic stress and lactation
There is evidence to suggest, at least in the European badger (Meles meles), that reduced nutrition of the dam lengthens diapause (Ferguson et al. 1996). In the classic paradigm of facultative diapause in rodents, mating occurs at a postpartum estrus, and implantation is delayed by the presence of suckling young, with larger litters causing a longer delay (Weichert 1940). In marsupials, the presence of suckling young, independent of number, represents the stimulus for entry and for maintenance of diapause, and removal of pouch young results in rapid reactivation of the embryo and consequent implantation (Renfree & Shaw 2000). Social stress, including crowding or introduction of new males, will induce facultative diapause in rodents (Marois 1982).
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Regulation by endogenous factors |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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Control by the pituitary gland
Regulation of embryonic diapause via hypophyseal prolactin demonstrates the principle that existing hormones have been co-opted for variable, often diametrically opposed, uses during evolution (Fig. 1). Prolactin is the key factor essential for embryo implantation in mustelid carnivores. Its circulating concentrations increase some days prior to implantation in both the mink (Murphy & Rajkumar 1985) and the spotted skunk (Mead 1993). Treatment of mink in diapause with prolactin precociously terminates diapause, while dopamine agonists, at doses that prevent prolactin secretion, prevent implantation (Papke et al. 1980). Withdrawal of the dopamine agonist (Papke et al. 1980) or administration of dopamine antagonists (Murphy 1983) terminates diapause in mink. Indeed, prolactin alone induced implantation in hypophysectomized mink (Murphy et al. 1981), as did administration of prolactin to animals in protracted diapause due to chronic melatonin treatment (Murphy et al. 1990). In macropod marsupials, prolactin plays an inhibitory role. In these species, hypophysectomy terminates diapause, and it has been shown that suckling-induced prolactin secretion during lactational delay prevents implantation (Renfree & Shaw 2000). During the seasonal delay in marsupials, a pulse of prolactin secretion is necessary for inhibition of implantation, and this pulse can be blocked by long photoperiods (Renfree & Shaw 2000).
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Ovarian events
Following ovulation in mustelids displaying an obligate diapause, the ovarian follicle collapses and forms the CL (Hanssen 1947). The CL body undergoes a remarkable structural reduction in size as diapause ensues, all the time secreting low levels of progesterone (Mead 1993, Murphy et al. 1993). In contrast to the pattern of terminal differentiation that characterizes CL development in most species, the mink CL retains its mitotic potential during the period of diapause (Douglas et al. 1998). In response to the pituitary prolactin signal that terminates diapause, the CL is rejuvenated, a process characterized by a several-fold increase in volume and in progesterone output (Murphy et al. 1993). In contrast to models of facultative delay, it has not been possible to terminate diapause in carnivores by steroid administration. Studies in the ferret (Foresman & Mead 1978) and mink (Murphy et al. 1983) indicated that a luteal protein in combination with progesterone are required for successful implantation. A credible candidate protein, glucose-6-phosphate isomerase also known as autocrine motility factor, has recently been shown to be secreted by the ferret CL during the appropriate pre-implantation window (Schulz & Bahr 2004) and to be required for implantation (Schulz & Bahr 2003). In mink, the activity of glucose-6-phosphate isomerase in circulation is low during diapause and increases with activation of the CL, and is elevated at the time of implantation (R D Bennett & B D Murphy, unpublished observations), suggesting that it might also play a role in reactivation of the mink embryo in diapause.
In marsupials, as exemplified by the wallaby, the CL develops during the estrous cycle, only to be inactivated by lactational or seasonal prolactin secretion (Renfree & Shaw 2000). Reactivation ensues when this inhibitory influence is removed. In rodents, it is the absence of an ovarian estrogen pulse that maintains diapause, but the ovarian structure (CL or follicle) from which the steroid issues has not been resolved.
The most unusual manifestation of ovarian regulation of diapause is found in the nine-banded armadillo. In this species, there appears to be no regression of the CL associated with delay, as indicated by plasma progesterone concentrations (Peppler & Stone 1980). Nonetheless, implantation is induced some 14 days after ovariectomy (Mead 1993), suggesting ovarian inhibition of nidation. The basis for this inhibition remains undiscovered.
Uterine factors
As noted above, reciprocal embryo transfers have demonstrated that the maternal uterine environment induces and maintains the embryo in its developmental arrest. An important question is whether diapause is due to the absence of uterine factor(s) necessary for development beyond the blastocyst, or whether the uterus actively maintains diapause by inhibition of development. Support for the former view can be found in studies that have shown large-scale increase in uterine protein synthesis and secretion concurring with the termination of obligate diapause (Mead 1989, Lambert et al. 2001). Furthermore, cascades in the synthesis of several classes of proteins, including adhesion factors, cytokines and growth factors, follow the estrogen pulse that induces mouse implantation (Dey et al. 2004). A simplified view of uterine and ovarian regulation of diapause in the embryo is presented in Fig. 2.
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Epidermal growth factor (EGF) is a potent mitogen, and thus a candidate for a uterine paracrine or autocrine factor regulating embryo mitosis. It can terminate diapause in ovariectomized rats in the absence of the estrogen pulse (Johnson & Chatterjee 1993), and members of the EGF family of growth factors, including heparin-binding EGF (hbEGF) and amphiregulin are expressed in overlapping patterns by the uterus during rodent implantation (Dey et al. 2004). The expression pattern of hbEGF at sites of implantation prior to embryo activation implicates it as a uterine factor effecting termination of diapause in rodents (Das et al. 1994). DNA microarray comparison of dormant and activated mouse blastocysts indicates that activation is associated with the expression of the gene encoding hbEGF, as well as the EGF receptor isoforms ErbB1 and ErbB4 (Hamatani et al. 2004). Further, hbEGF expression is induced in the uterus by estrogen (Zhang et al. 1998), the proximal signal for the termination of diapause. In addition, EGF receptors are present in dormant carnivore embryos, and their signaling activity is increased associated with escape from diapause (Paria et al. 1994). It is therefore reasonable to speculate that estrogen-induced expression of EGF and EGF-like factors from the uterus and embryo, acting on cognate receptors in the blastocyst, reinitiates development.
Microarray analysis comparing the mouse uterus before and after the nidatory estrogen pulse indicates upregulation of other growth factor-related transcripts (Reese et al. 2001). A pentraxin family protein (PTX3) is expressed at nearly fourfold greater intensity in the post-delay uterus. This protein is involved in complement binding and in innate immune responses, and is secreted in response to inflammatory cytokines (Fulop et al. 2003). PTX3 gene deletion disrupts ovarian function by interfering with cumulus formation (Fulop et al. 2003). While there are no investigations of its role in termination of diapause, its expression pattern and its known role in glycoprotein synthesis identify it as a potential downstream target of the growth factor and cytokine cascade that terminates embryo arrest.
There is evidence to suggest that the uterus actively inhibits development of the embryo, thereby inducing and maintaining diapause. Flushings from the uteri of ovariectomized, progesterone-treated mice (the delayed implantation model) contain protein fractions that inhibit DNA synthesis of embryos in vitro (Weitlauf 1978). Recent studies have revealed that the endogenous cannabinoid, anandamide, at high, but nonetheless physiologically relevant, concentrations inhibits mouse embryo development (Wang et al. 2003). Low levels of anandamide, in stark contrast, activate the dormant mouse blastocyst via mitogen-activated kinase pathways. Thus, differential expression of cannabinoids may regulate facultative diapause.
Uterine microarray analysis indicates that several interferon-
induced genes are downregulated in the activated, relative to the delayed mouse uterus (Reese et al. 2001), suggesting that this cytokine might play a role in induction or maintenance of mitotic quiescence of the embryo.
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Regulation of diapause by cellular factors |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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By definition, the quiescent embryonic cells also retain the ability to resume the cell cycle when diapause terminates (Renfree & Shaw 2000). In the mouse, proliferation is initiated first in the inner cell mass of the blastocyst, almost immediately after the estrogen signal, and follows 6–12 h later in the trophoblast (Given & Weitlauf 1981). An intriguing new report suggests that reactivation of development in the trophoblast compartment of the spotted skunk embryo engenders endocycles, resulting in endopolyploidy (Isakova & Mead 2004). The significance of this finding to the termination of diapause awaits further investigation.
Cell cycle arrest has not been extensively studied in the mammalian embryo in diapause. Given the conservation of genes during evolution, investigations of diapause in invertebrate and sub-mammalian vertebrate models might be expected to provide insight into the maintenance of mammalian diapause. It has been shown that, in the fruit fly (Drosophila melanogaster), the developmental arrest during embryogenesis can be attributed to the dacapo gene, homolog of the mammalian p21, an inhibitor of cyclin E–cdk2 complex activation (Lane et al. 1996). This is consistent with inhibition in G1, as cyclin E–cdk2 complex formation is necessary for entry into S phase. Other candidate genes for inhibition of the cell cycle in diapause have been derived from cDNA microarray and subtractive hybridization comparisons of embryos in diapause with their activated counterparts. In insects, proliferating cell nuclear antigen (PCNA), a factor associated with DNA synthesis and regulated by p21 (Fotedar et al. 2004), is not expressed during diapause (Denlinger 2002). These findings are consistent with new information from the mouse embryo where dormancy is associated with the increased expression of p21cip1/WAF1 and concomitant decrease in a number of DNA replication genes (Hamatani et al. 2004). These studies also demonstrated that an inhibitor of G0/G1 transition, the B cell translocation gene 1 (Btg1 (Rouault et al. 1992)) is upregulated in the embryo during facultative diapause, providing a mechanism for maintenance of cell arrest. Expression of the classic cell cycle inhibitor p53 and associated genes did not differ between dormant and activated mouse embryos, suggesting that this common effector of cell cycle arrest is not involved in diapause (Hamatani et al. 2004).
Regulation of the cell cycle in diapause and reactivation
Given the variation among mammalian groups displaying embryonic diapause, there may be no single mechanism of reactivation of mitosis. In non-mammalian models, several different proximal signals (temperature, photoperiod, nutrient supply) regulate cell cycle arrest and reactivation. In insects, reduction in ambient temperature induces a decline in ecdysteroid concentrations that in turn signals the initiation of diapause (Denlinger 2002). The earliest intracellular response detected to environmental stimuli that terminate diapause, including increasing temperature, is upregulation of synthesis of ecdysone and expression of its nuclear receptor (Denlinger 2002). In the nematode, Caenorhabditis elegans, multiple signals inducing the dauer diapause converge on daf-12, a nuclear receptor for a yet-unknown sterol ligand (Gerisch & Antebi 2004). In this species, termination of diapause engenders downregulation of daf-9, a P450 hydroxylase that catalyzes formation of the ligand. Thus, a common theme emerges of termination of diapause in invertebrates by cholesterol or its derivatives, acting through classic nuclear receptor pathways.
Vertebrates have evolved to employ specific cholesterol derivatives, the steroids, in the regulation of reproduction. In all known examples of mammalian diapause, with the possible exception of the armadillo, ovarian progesterone is essential for the termination of delay (Mead 1993). Further, a single estrogen injection terminates diapause in rodents (Dey et al. 2004). Treatment of carnivores in obligate (Murphy et al. 1982) or marsupials in seasonal (Fletcher et al. 1988) delay with estrogen does not induce reactivation of the embryo. Nonetheless, estrogens have pleiotropic mitogenic and mitotic effects on target tissues, mediated through classic nuclear receptors, membrane estrogen receptors and actions of multiple intracellular effectors (Frasor et al. 2003) and may, in the appropriate concentration and temporal sequence, reactivate embryos in diapause. Estrogen receptors (ER) are expressed in all cell types of the dormant and activated mouse blastocyst (Hou et al. 1996) and both nuclear receptor subtypes, ER
and ERß, have been identified in the cells of the blastocyst in diapause (Paria et al. 1998). Treatment of mice in delay of implantation with estradiol-17ß resulted in S-phase activity in the embryos at the earliest time tested, 6 h (Given & Weitlauf 1981), and a detectable increase in the cell number within 12 h (Spindler et al. 1996). Paria et al.(1998) report that the principal mammalian estrogens, estradiol-17ß, estrone and estriol, do not directly activate the dormant mouse embryo. This was concluded because estradiol-17ß failed to induce the expression of EGF binding to the embryo, the hallmark of embryo activation, and blastocysts treated with estrogen in vitro failed to implant. These findings notwithstanding, it remains likely, based on the temporal sequence of occurrence of the S phase after estrogen treatment, that estrogens function as mitogens to terminate cell cycle arrest. The effects of estrogens may not be mediated through the classic nuclear receptors. Paria et al.(1998) make a case for embryo activation (EGF signaling) by uterus-derived catechol estrogens, signaling via a non-genomic pathway. EGF is a potent mitogen, and there is evidence for non-genomic signaling between estrogen-and EGF-mediated cellular events (Driggers & Segars 2002). A plausible hypothesis is that mitosis is reinstated in the embryo by EGF as a downstream event induced by primary estrogen or catechol estrogen signaling.
Clues to the intracellular events in mitotic renewal can be derived from comparison of the transcriptome between dormant and activated mouse embryos (Hamatani et al. 2004). There is upregulation of the estrogen-responsive target, Brca1, a gene that promotes proliferation in other tissues (Deans et al. 2004). Dormant embryos have greater abundance of the histone deacetylase-5 (HDAC-5) transcript, a gene whose expression is associated with attenuation of proliferation, and is independent of p53 mechanisms (Huang et al. 2002). The mitotic stimulus downregulates this chromatin modifier, allowing for histone acetylation and consequent transcription of previously silenced genes.
Comparative models provides some insight into potential regulation of mitotic re-initiation at the end of diapause. The FoxO genes are the mammalian orthologs of the C. elegans Daf genes that regulate diapause (Hosaka et al. 2004). Among the roles played by FoxO transcription factors in C. elegans is the induction of p21 expression and consequent mitotic arrest (Seoane et al. 2004). Indeed, overexpression of FoxO transcription factors induces cell cycle arrest at the G1 phase in mammalian cells in vitro (Burgering & Kops 2002). Although null mutation of FoxO1, 2 or 3 does not interfere with early embryo development or implantation in mammals, ovarian function is disrupted in FoxO3a null mice, with a phenotype of proliferation of the granulosa component of an abnormal number of follicles and consequent precocious depletion of the follicle population (Hosaka et al. 2004). Thus, FoxO-induced cell cycle inhibition may be an important mechanism in the maintenance of diapause. Recent studies have further defined a mechanism of escape from FoxO-induced inhibition of proliferation. Phosphorylation of FoxO genes occurs in response to mitogens, including estrogen (Birkenkamp & Coffer 2003). This modification restricts their translocation to the nucleus, thereby abrogating their cytostatic effects (Seoane et al. 2004). Further investigation is required to verify this hypothesis.
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Summary and conclusions |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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). Based on non-vertebrate models, a case is made for transcriptional regulation of cell cycle inhibitors by the forkhead family of transactivators, inactivated by mitogenic stimulation.
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Acknowledgements |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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Footnotes |
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References |
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TopAbstractIntroductionThe embryo in diapauseTwo variations on the...Regulation of diapause by...Regulation by endogenous factorsRegulation of diapause by...Summary and conclusionsAcknowledgementsReferences |
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