Gene name - Cyclin A
Cytological map position - 68E1--68E2
Function - Activates cdc2 kinase
Keywords - cell cycle
Symbol - CycA
Genetic map position - 3-
Classification - G2-M cyclin
Cellular location - nuclear
|Recent literature||Afonso, D.J., Liu, D., Machado, D.R., Pan, H., Jepson, J.E., Rogulja, D. and Koh, K. (2015). TARANIS functions with Cyclin A and Cdk1 in a novel arousal center to control sleep in Drosophila. Curr Biol [Epub ahead of print]. PubMed ID: 26096977
Sleep is an essential and conserved behavior whose regulation at the molecular and anatomical level remains to be elucidated. This study identifies Taranis (Tara), a Drosophila homolog of the Trip-Br (SERTAD) family of transcriptional coregulators, as a molecule that is required for normal sleep patterns. Through a forward-genetic screen, tara was isolated as a novel sleep gene associated with a marked reduction in sleep amount. Targeted knockdown of tara suggests that it functions in cholinergic neurons to promote sleep. tara encodes a conserved cell-cycle protein that contains a Cyclin A (CycA)-binding homology domain. Tara regulates CycA protein levels and genetically and physically interacts with CycA to promote sleep. Furthermore, decreased levels of Cyclin-dependent kinase 1 (Cdk1), a kinase partner of CycA, rescue the short-sleeping phenotype of tara and CycA mutants, while increased Cdk1 activity mimics the tara and CycA phenotypes, suggesting that Cdk1 mediates the role of Tare and CycA in sleep regulation. Finally, a novel wake-promoting role was described for a cluster of ∼14 CycA-expressing neurons in the pars lateralis (PL), previously proposed to be analogous to the mammalian hypothalamus. The study proposes that Taranis controls sleep amount by regulating CycA protein levels and inhibiting Cdk1 activity in a novel arousal center.
|Bourouh, M., Dhaliwal, R., Rana, K., Sinha, S., Guo, Z. and Swan, A. (2016). Distinct and overlapping requirements for Cyclins A, B and B3 in Drosophila female meiosis. G3 (Bethesda) [Epub ahead of print]. PubMed ID: 27652889
Meiosis, like mitosis depends on the activity of the mitotic Cyclin dependent kinase, Cdk1 and its cyclin partners. This study examined the specific requirements for the three mitotic cyclins, Cyclin A, Cyclin B and Cyclin B3 in meiosis of Drosophila melanogaster. All three cyclins were found to contribute redundantly to nuclear envelope breakdown, though Cyclin A appears to make the most important individual contribution. Cyclin A is also required for bi-orientation of homologues in meiosis I. Cyclin B3, as previously reported, is required for anaphase progression in meiosis I and in meiosis II. Cyclin B3 also plays a redundant role, with Cyclin A, in preventing DNA replication during meiosis. Cyclin B is required for maintenance of the metaphase I arrest in mature oocytes, for spindle organization and for timely progression through the 2nd meiotic division. It is also essential for polar body formation at the completion of meiosis. With the exception of its redundant role in meiotic maturation, Cyclin B appears to function independently of Cyclins A and B3 through most of meiosis. The study concludes that the 3 mitotic Cyclin-Cdk complexes have distinct and overlapping functions in Drosophila female meiosis.
In Drosophila, Cyclin A and Cyclin B appear to be functionally indistinguishable. However, differences between these cyclins exist, with respect to distribution and degradation patterns. The functional overlap between Cyclin A and B, both of which regulate the cyclin dependent kinase cdc2, is discussed in the Cyclin B site.
Following cellularization, Cyclin B, like Cyclin A accumulates during G2. Cyclin A distribution peaks in prophase, and then declines. In contrast, Cyclin B is maintained at its maximum from prophase until metaphase. Prophase cells often show a more uniform distribution of Cyclin B throughout the cell, and degradation of the protein does not occur until the metaphase-anaphase transition, well after the disappearance of Cyclin A. The accumulation and degradation of Cyclin A is similar in both colchicine treated cells and untreated control cells. However, Cyclin B accumulation seems to be independent of spindle function, and its degradation is inhibited by colchicine treatment (Whitfield, 1990). Expression of a modified form of Cyclin A, which cannot be degraded during mitosis, reveals that persistence of Cyclin A delays metaphase, suggesting a requirement for the degregadation of Cyclin A before entry into mitosis. Persistence of Cyclin B, whose degradation is required for completion of mitosis, does not effect entry into mitosis. Persistence of Cyclin A also results in abnormal spindle structures (Sigrist, 1995).
As with Cyclin B, a review of vertebrate studies highlights the functional differences between Cyclin A and B. From such perspectives, the two cyclins appear to be functionally worlds apart. Cyclin A plays a dual role in vertebrates, involved in both S phase and in the G2-M transition. In association with E2F it helps to terminate activation of the transcription of genes involved in DNA replication. Later in the cycle, depletion of Cyclin A arrests cells in G2. Thus Cyclin A is required for progression from G2 to M (Pagano, 1992). In Drosophila, no S phase role has been detected for Cyclin A. The requirement for Cyclin A in the G2-M phase transition is not well characterized: the targets are not yet known. Cyclin A peaks in prophase and then declines. These kinetics suggests little if any involvement of Cyclin A in the metaphase/anaphase checkpoint (see Cyclin B), but is consistent with an earlier requirement for the onset of mitosis.
In fly embryos, Cyclin E is the normal inducer of S phase in G1 cells. Stable G1 quiescence requires the downregulation both of cyclin E and of other factors that can bypass the normal regulation of cell cycle progression. High-level expression of cyclin A triggers the G1/S transition in wild-type embryos and in mutant embryos lacking cyclin E. Three types of control downregulates this activity of cyclin A: (1) cyclin destruction limits the accumulation of cyclin A protein in G1; (2) inhibitory phosphorylation of cdc2, the kinase partner of cyclin A, reduces the S-phase promoting activity of cyclin A in G1 and (3) Roughex (Rux), a protein with unknown biochemical function, limits cyclin A function in G1. Overexpression of rux blocks S phase induction by coexpressed cyclin A and promotes the degradation of cyclin A. Rux also prevents a stable cyclin A mutant from inducing S phase, indicating that inhibition does not require cyclin destruction. This inhibition also drives the nuclear localization of stable cyclin A. It is therefore considered likely that Roughex effects on the nuclear translocation of cyclin A would target cyclin A for degradation. It is concluded that cyclin A can drive the G1/S transition, but this function is suppressed by three types of control: cyclin A destruction, inhibitory phosphorylation of cdc2, and inhibition by Rux. The partly redundant contributions of these three inhibitory mechanisms safeguard the stability of G1 quiescence until the induction of cyclin E. The action of Rux during G1 resembles the action of inhibitors of mitotic kinases present during G1 in yeast, although no obvious sequence similarity exists (Sprenger, 1997).
Studies of the grapes (grp) gene, which encodes a homolog of the Schizosaccharomyces pombe Chk1 kinase, provide clues about the role of Cyclin A in coordinating mitotic events early in Drosophila development. Grapes is known to regulate a cell-cycle checkpoint that delays mitosis in response to inhibition of DNA replication. Grp is also required in the undisturbed early embryonic cycles: in its absence, mitotic abnormalities appear in cycle 12 and chromosomes fail to fully separate in subsequent cycles. In other systems, Chk1 kinase phosphorylates and suppresses the activity of the Cdc25 phosphatase String: the resulting failure to remove inhibitory phosphate from cyclin-dependent kinase 1 (Cdk1) prevents entry into mitosis. Because in Drosophila embryos Cdk1 lacks inhibitory phosphate during cycles 11- 13, it is not clear that known actions of Grp/Chk1 suffice in these cycles. In early cell cycles, the loss of grp compromises Cyclin A proteolysis and delays mitotic disjunction of sister chromosomes. These defects occur prior to previously reported grp phenotypes. It is concluded that Grp activates Cyclin A degradation, and functions to time the disjunction of chromosomes in the early embryo. As Cyclin A destruction is required for sister chromosome separation: a failure in Grp-promoted cyclin destruction can also explain the mitotic phenotype. The mitotic failure described previously for cycle 12 grp embryos might be a more severe form of the phenotypes that are describe here in earlier embryos and it is suggested that the underlying defect is reduced degradation of Cyclin A (Su, 1999).
When syncytial embryos are exposed to cycloheximide, a protein synthesis inhibitor, nuclear cycles arrest in interphase and cyclin A levels decline whereas Cyclin B is stable under these conditions. This suggests that a steady state of synthesis and degradation maintains the interphase levels of Cyclin A during the syncytial divisions. grp mutants were found to be deficient in Cyclin A degradation in the presence of cycloheximide. This defect is seen in embryos in cycles 4- 8, earlier than other reported grp phenotypes and is therefore unlikely to be secondary to these phenotypes. It is inferred that Grp normally destabilizes Cyclin A (Su, 1999).
In wild-type embryos, Cyclin A is unstable not only in interphase but also during mitotic arrest caused by microtubule destabilization. Thus, in embryos treated with colchicine, blocking protein synthesis with cycloheximide leads to a decline in Cyclin A levels, whereas cyclin B is stable under these conditions. grp embryos are compromised for Cyclin A proteolysis at such a colchicine-induced mitotic arrest. As for interphase destruction of Cyclin A, this defect is seen during early syncytial cycles, before the onset of other reported grp phenotypes. It is concluded that Grp promotes Cyclin A degradation in colchicine-arrested early embryos (Su, 1999).
If normal levels of Cyclin A are maintained by a steady state of synthesis and destruction, it would be expected that the levels of Cyclin A would be high in grp embryos as a result of increased stability. Western blotting shows that grp embryos have slightly higher levels of Cyclin A than wild-type embryos (1.5-3-fold). Although this relatively small increase suggests that significant degradation of Cyclin A still occurs in grp embryos, this degradation is not apparent at the arrests induced by cycloheximide or by colchicine (Su, 1999).
Since Grp is required for destruction of Cyclin A in an arrested mitosis, it was determined whether or not mitosis is disrupted in grp embryos. The mitosis-specific phosphorylation of histone H3 (PH3) apparently acts as an in vivo reporter for cyclin/Cdk activity and its disappearance at the end of mitosis requires cyclin destruction. During syncytial cycles of wild-type embryos, PH3 staining is continuous along the length of the chromosome arms from metaphase until late anaphase, when loss of the epitope near kinetochores leads to graded staining. In embryos from grp1 homozygous females or from grp1/Df females, the gradient of PH3 is seen on chromosomes in early anaphase. Thus, PH3 loss is advanced with respect to chromosome segregation in grp embryos. This defect is seen at the earliest cycles scored (cycle 4 in grp1/grp1 and cycle 3 in grp1/Df), well before the onset of previously reported defects in grp embryos (cycle 11) (Su, 1999).
The loss of PH3 during early anaphase in grp embryos could be due to the premature loss of PH3, a scenario opposite of that expected for a mutation that stabilizes Cyclin A during mitosis. Alternatively, timely loss of PH3 staining but delayed chromosome separation would produce the same mis-coordination. Analysis of grp embryos supports the latter hypothesis: an increase in the ratio of embryos with unsegregated chromosomes (prophase/metaphase) to those with segregated chromosomes (anaphase/telophase) has been found. It ia concluded that Grp is required for timely chromosome segregation in syncytial mitoses (Su, 1999).
The mitotic phenotype in grp embryos can be understood as follows: ordinarily, the mitotic cyclins are degraded in a sequence during exit from mitosis; Cyclin A is degraded before the metaphase-anaphase transition; cyclin B is degraded at the beginning of anaphase and cyclin B3 towards the end of anaphase. The disappearance of PH3 can be prevented by stabilization of any of these mitotic cyclins; thus, it appears that loss of PH3 marks the completion of this sequence. It is suggested that grp embryos are specifically defective in the early initiation of Cyclin A degradation but they do degrade Cyclin A, perhaps in conjunction with the B cyclins. Eventual destruction of Cyclin A would explain the ability of grp-deficient nuclei to exit mitosis and lose PH3 staining, events that can be inhibited by stable Cyclin A. Destruction of Cyclin A in conjunction with the B cyclins would explain why the length of mitosis is not increased in grp embryos. Because the expression of a stable form of Cyclin A prevents chromosome disjunction, it has been suggested that the failure to degrade Cyclin A early during mitosis in grp embryos delays chromosome disjunction. The delay in chromosome separation abbreviates anaphase and, when the abbreviation is severe, decondensation of chromosomes and entry into the next interphase occurs before the separating chromosomes reach the spindle poles (Su, 1999).
Since Grp promotes Cyclin A degradation, genetic interactions might be detected between grp and Cyclin A. A test was performed to see whether grp mutants are sensitive to levels of Cyclin A. Homozygous grp flies are viable but female sterile. When a single copy of a heat-inducible Cyclin A transgene is introduced, however, homozygous grp1 progeny are not recovered. Thus, even without induction, the presence of a heat-inducible Cyclin A transgene (which by itself is viable as a heterozygote or homozygote) causes grp1 to behave as a recessive lethal. The observed synthetic lethality suggests that the Grp deficiency sensitizes the fly to low levels of Cyclin A expression from the transgene. In contrast to this strong interaction with increased Cyclin A levels, a reduction in the dose of Cyclin A fails to suppress the grp1 allele. It is perhaps not surprising that reduction of Cyclin A by half does not suppress a null allele of grp. Reduction in the dose of Cyclin A does suppress the lethality of mei-41 mutations. The mei-41 gene is a homolog of the gene ATM, which is mutated in the genetic disorder ataxia-telangiectasia; mei-41 is thought to act upstream of grp in the checkpoint pathway, and mutations in mei-41 result in a phenotype like grp, but less severe. Importantly, the suppression of the mei-41 embryonic lethality by cyclin reduction occurs without restoring interphase length. This result shows that the mitotic defect is not an inevitable consequence of premature entry into mitosis as previously thought. It is suggested that the mitotic defect is an anaphase failure as a result of defective metaphase destruction of Cyclin A (Su, 1999).
If Grp promotes the metaphase-anaphase transition, why is it dispensable at most stages of development? Before cell cycle 12, grp embryos exhibit a defective mitosis with delayed sister chromosome separation; despite this, mitosis is successful. From this observation, two inferences can be made: (1) mitosis can tolerate a limited disruption in the timing of events and, (2) as anaphase occurs in the absence of Grp, there must be a backup Grp-independent mechanism that promotes sister separation slightly later. The mitotic mis-coordination in grp embryos gets progressively more severe, and Cyclin A levels increase progressively during the syncytial cycles. This correlation, together with the ability of reduced Cyclin A dose to suppress mei-41 lethality, leads the authors to suggest that the consequence of a defect in the grp/mei-41 pathway increases in severity as Cyclin A increases, until anaphase fails at mitosis 12 and 13 (Su, 1999).
The current model for Chk1 function involves the phosphorylation and inhibition of Cdc25, in part by the binding of 14-3-3 protein to the phosphorylated Cdc25 and sequestration in the cytoplasm where it is ineffective in counteracting the nuclear kinases Wee1 and Mik1. Thus, inhibitory phosphorylation of Cdk1 prevents its activation and the cell arrests in G2. Although this action of Chk1 appears general, it is possible that Chk1 activity has other consequences. Indeed, there is no substantial accumulation of inhibitory phosphate on Cdk1, and the Cdc25Stg protein is constitutively present and nuclear during interphase of syncytial cycles 11- 13 when a grp-dependent mechanism regulates the entry into mitosis. The results presented here suggest that Grp may function to destabilize Cyclin A. When a Grp-dependent cell-cycle checkpoint is induced by blocking S phase with aphidicolin in cleavage-stage Drosophila embryos, Cdc25Stg is destabilized. Thus, whether it is direct or indirect, Grp promotes the destruction of two cell-cycle proteins, Cdc25Stg and Cyclin A. It is suggested that promotion of the metaphase- anaphase transition represents a second function of the grp/mei-41 pathway, distinct from the checkpoint arrest of entry into mitosis. Nevertheless, a common mechanism might be involved because blocking entry into mitosis and promoting exit from mitosis both involve inhibition of cyclin/Cdk1 activity (Su, 1999).
In summary, Grp is required for normal Cyclin A turnover in the early Drosophila embryo. It was also found that grp mutant embryos show a delay in the timing of the metaphase- anaphase transition. Stable versions of Cyclin A block chromosome separation at the metaphase plate, at least in cellularized Drosophila embryos, suggesting that proteolysis of Cyclin A is required for this process. Thus, the proposal that Grp activates Cyclin A proteolysis can explain the mitotic phenotype as a consequence of at least temporary persistence of Cyclin A (Su, 1999).
How and why the brain reversibly switches from a waking to a sleep state remain among the most intriguing questions in biology. This study shows that cyclin A (CycA) and regulator of cyclin A1, essential cell cycle factors, function in postmitotic neurons to promote sleep in Drosophila melanogaster. Reducing the abundance of CycA in neurons delayed the wake-sleep transition, caused multiple arousals from sleep, and reduced the homeostatic response to sleep deprivation. CycA is expressed in ~40 to 50 neurons in the adult brain, most of which are intermingled with circadian clock neurons, suggesting functional interactions among neurons controlling sleep and circadian behavior (Rogulija, 2012).
Prolonged intervals of rest in Drosophila share many features with mammalian sleep. Flies spend a large portion of their waking time moving, and the locomotor assay developed for circadian behavior can therefore be used to screen for sleep mutants in this animal. A bout of inactivity lasting 5 min or longer is associated with an increased arousal threshold, as well as changes in neural activity, and is used to define sleep in the fly. Since the discovery of sleep in Drosophila a decade ago, the results of several genetic screens for sleep factors have been reported, and many of the genes identified have conserved roles across species. A surprisingly large fraction of these genes are ion channels or their regulators, or are involved with broadly acting neurotransmitter pathways. These findings led to the hypothesis that there are no dedicated sleep genes but rather that sleep is regulated by genes that control normal neuronal function (Rogulja, 2012).
This study carried out a screen for sleep genes solely within the nervous system, bypassing the potential confounding effects of these genes in other tissues. ~4000 UAS-RNA interference (UAS-RNAi) lines were screened using the pan-neuronal driver elavGal4 to knock down gene expression, while simultaneously driving the expression of UAS-Dicer2 to enhance RNAi efficacy. After three retesting rounds, ~20 genes were identified whose RNAi-mediated neuronal depletion led to reproducible changes in sleep pattern, quantity, or both. One sleep-promoting factor isolated was Rca1 (regulator of cyclin A1
Depletion of Rca1 from neurons (elavGal4 + UAS-Rca1-RNAi, denoted 'elav>Rca1-RNAi') decreased the amount of total daily sleep, without affecting the levels of activity per waking minute. It did so by decreasing the duration of individual sleep episodes (sleep bouts). The number of sleep episodes was slightly increased in elav>Rca1-RNAi animals, likely because of the highly fragmented nature of their sleep. The net reduction in sleep duration understates the severity of the elav>Rca1-RNAi phenotype. For example, elav>Rca1-RNAi flies that showed no net change in daily sleep often failed to display behavior that is organized into prolonged intervals of rest and activity seen in the control flies (Rogulja, 2012).
Drosophila Rca1 is homologous to the mammalian early mitotic inhibitor (Emi1) and plays a critical role in preventing premature cyclin degradation. Cyclins regulate cell cycle progression through activation of specific cyclin-dependent kinases (CDKs). The main target of Drosophila Rca1 regulation is cyclin A (CycA), so tests were performed to see whether depletion of CycA might affect sleep. Indeed, expression of CycA-RNAi in neurons (elavGal4 + UAS-CycA-RNAi, denoted 'elav>CycA-RNAi') caused a decrease in the time animals spent sleeping without significantly affecting levels of activity per minute while awake. This reduction was a consequence of decreased sleep bout duration, whereas the number of sleep episodes was slightly increased (Rogulja, 2012).
It was noticed that the ectopic overexpression of Rca1 or CycA in neurons produced a small and rough eye phenotype. A similar eye phenotype is associated with a mutation in a negative regulator of CycA and was used in a modifier screen to identify new genes involved in cell cycle regulation. This morphological readout of CycA abundance was used to confirm that the UAS-Rca1-RNAi and UAS-CycA-RNAi lines were effective, by showing that they suppressed eye phenotypes associated with Rca1 or CycA overexpression, respectively. Furthermore, UAS-Rca1-RNAi also suppressed the eye phenotypes resulting from CycA overexpression, indicating that Rca1 can stabilize CycA protein in neurons (Rogulja, 2012).
Flies homozygous for CycA null alleles (CycA-) do not survive and could not be examined. However, CycA- heterozygotes are viable and showed a decrease in total sleep amounts, a phenotype further enhanced by expression of CycA-RNAi in this background, even in the absence of Dicer2 overexpression. An additive effect was observed between the heterozygous CycA- mutation and neuronal Rca1-RNAi as well. The reduction in total sleep seen in these experiments may not fully reflect the influence of CycA and Rca1 in sleep control, as CycA protein was still detectable in the brains of all of the experimental genotypes (Rogulja, 2012).
As CycA is thought to be the main target of Rca1 regulation during the cell cycle, and behavioral and genetic analyses indicated a similar relation with respect to the effects of these genes on sleep, focus was placed on CycA for subsequent studies (Rogulja, 2012).
It took significantly longer for elav>CycA-RNAi flies to fall asleep after lights went off than it did for the controls. This was not the case for all genes that were identified in the screen. This increased latency to sleep suggests that a mechanism regulating wake-sleep transition is disrupted in elav>CycA-RNAi flies. To determine if sleep can be homeostatically controlled in these animals, their response to sleep deprivation was examined. The flies were mechanically stimulated during the night, and their sleep pattern was examined during the subsequent morning, when 'rebound' sleep is normally seen in wild-type flies that have been sleep-deprived the night before. Although some increase was seen in rebound sleep in flies of all the genotypes tested, this response was reduced in elav>CycA-RNAi flies, suggesting a defective sleep homeostat. In accordance with the idea that sleep serves an essential function, neuronal depletion of CycA shortens life span, presumably due to chronic sleep deprivation experienced by these animals. However, it is also possible that CycA contributes to life span through other functions in postmitotic neurons (Rogulja, 2012).
Sleep is regulated in a circadian fashion, so it was asked whether some of the sleep defects observed in elav>CycA-RNAi animals resulted from a disrupted circadian clock. Most elav>CycA-RNAi flies showed robust rhythms in constant darkness, with normal periods. Circadian rhythmicity was observed even in animals with severe sleep defects. Furthermore, elav>CycA-RNAi flies eclosed with strong circadian rhythms. Finally, Period (PER), a core component of the circadian clock, accumulated rhythmically in the pacemaker neurons of elav>CycA-RNAi animals. Thus, the sleep defects observed in elav>CycA-RNAi animals appear not to reflect circadian clock anomalies (Rogulja, 2012).
Staining with two different antibodies to CycA showed a restricted expression pattern in adult brains. Both antibodies detected the same ~12 dorsal neurons, and one of the antibodies labeled cells in several other brain regions, including the pars intercerebralis, a known fly sleep center. The antibody that detected CycA in more cells was raised against the whole CycA protein, whereas the one that labeled fewer cells was raised against the CycA N terminus. Both appear to be specific to CycA, because their staining was strongly reduced in embryos in which CycA-RNAi was driven by a strong, ubiquitous Gal4 driver. The broader CycA expression pattern in the brain was supported by colocalization with CycAGal4-driven GFP, although GFP was detected in additional cells in all the clusters. Overall, CycA protein was detected in ~40 to 50 neurons in the brain (Rogulja, 2012).
In the adult fly brain, ~150 clock neurons are organized into six major clusters: three dorsal clusters (DN1, DN2, and DN3), a dorsal-lateral cluster (LNd), and two groups of ventral-lateral neurons -- small (s-LNv) and large (l-LNv). The small and large ventral-lateral neurons include neurons that produce the neuropeptide pigment dispersing factor (PDF), a major regulator of clock output. s-LNvs are the major pacemaker neurons which also regulate sleep. Costaining of brains for CycA and PDF revealed that termini of PDF-producing s-LNvs project near the dorsal CycA neurons. Indeed, as judged by PDFrGal4-driven GFP, which marks presumptive PDF receptor-producing neurons, these CycA cells appear to express the PDF receptor. Such coexpression was found in all CycA neurons and suggests a molecular and neuronal connection between circadian and sleep systems. Coexpression with PDFr also provides an opportunity to knock down CycA abundance in a more limited set of neurons than the pan-neuronal driver affords. PDFrGal4-driven CycA-RNAi results in a severe sleep reduction (Rogulja, 2012).
To determine if dorsal CycA neurons are in fact DN1 circadian neurons, it was asked whether they express per. A subset of the dorsal CycA-containing neurons expressed perGal4-driven GFP. A similar partial overlap was seen in all other CycA clusters, with the exception of the pars intercerebralis. As perGal4 was expressed in a smaller subset of CycA neurons than PDFrGal4, the former was used to knock down CycA in a more limited neuronal subpopulation. In these experiments, sleep was consistently lower than in control animals, although the extent of sleep loss was less extreme than with pan-neuronal CycA knockdown. Notably, CycA-containing dorsal neurons that expressed perGal4 were not stained by an antibody to PER, and thus do not detectably express PER protein. Therefore, dorsal CycA neurons are closely associated with the DN1 cluster, but do not appear to be clock neurons themselves. A similar relationship exists between CycA-expressing and DN3 or LNv neurons. In contrast, CycA and PER proteins were occasionally found in the same cell within a subset of dorsal-lateral neurons (LNds), a group of clock neurons that regulate the evening peak of activity. Finally, a bilaterally symmetric pair of large ventral neurons expressed both CycA and PER proteins. These ventral neurons do not belong to any known clock neuronal clusters. In summary, CycA-containing neurons are often intermingled with circadian pacemaker neurons. As CycA neurons appear to express the receptor for the circadian neuropeptide PDF, such an arrangement suggests that signals produced by neurons regulating circadian rhythmicity may be directed to neurons that control sleep (Rogulja, 2012).
There are other known instances of the repurposing of cell cycle machinery in neurons. Examples include the recent observations that two CDK pathways are essential for proper axonal targeting of presynaptic components in Caenorhabditis elegans, and that cyclin E regulates synaptic plasticity and memory formation in mice. No obvious defects were observed in the gross morphology or number of CycA-containing neurons in elav>CycA-RNAi flies, no obvious rhythmic patterns of CycA protein expression were detected. Nevertheless, such features might become evident in studies focused on specific cells or specific subcellular regions, or in developing or aging flies. Future understanding of the role that CycA plays in determining the structure or activity of neurons specialized for the regulation of sleep seems likely to shed light on the molecular mechanisms underlying this enigmatic behavior. As the role of CycA in cell cycle regulation is conserved throughout metazoans, its role in sleep regulation might be conserved as well (Rogulja, 2012).
Bases 5' UTR - 298+
Bases 3' UTR - 670
In aligned fly and clam Cyclin A sequences within a 60 amino acid region, residues at 82% of the positions are similar and 72% are identical. Within this same region, 47% of the positions are identical among all the cyclins, whether A or B type, or whether of yeast, mollusc, echinoderm or insect origin. Conservation among this group of proteins extends throughout the carboxy-terminal two-thirds of these proteins (Lehner, 1989).
date revised: 15 Nov 97
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