The phenotypes of the mr mutations indicate that the gene is required for cell cycle regulation throughout development: during adult oogenesis, in the early S-M embryonic cycles, in larval endo cycles, and in mitotically dividing larval tissues. The expression pattern of the gene was examined by hybridizing the insert from a mr cDNA to a Northern blot with RNA isolated from different developmental stages. This experiment shows that the mr gene is expressed throughout development, but, interestingly, three different transcript forms are present, and these show different developmental regulation. There is an abundant transcript of ~2.5 kb present in adult females and early embryos, most likely the form expressed during oogenesis and deposited into the developing oocyte. In larval development, transcripts of 2.9 and 3.2 kb become more prevalent, and in adult males solely the 3.2-kb transcript is detectable. The cDNAs recovered by the genome project from embryonic libraries all encode one protein form and are likely to represent the transcript that experimentally measures 2.5 kb. Additional analyses will be required to determine whether the three transcript forms arise from distinct promoters or alternative processing, and whether these result in alternative forms of the protein (Kashevsky, 2002).
Neuronal plasticity relies on tightly regulated control of protein levels at synapses. One mechanism to control protein abundance is the ubiquitin-proteasome degradation system. Recent studies have implicated ubiquitin-mediated protein degradation in synaptic development, function, and plasticity, but little is known about the regulatory mechanisms controlling ubiquitylation in neurons. In contrast, ubiquitylation has long been studied as a central regulator of the eukaryotic cell cycle. A critical mediator of cell-cycle transitions, the anaphase-promoting complex/cyclosome (APC/C), is an E3 ubiquitin ligase. Although the APC/C has been detected in several differentiated cell types, a functional role for the complex in postmitotic cells has been elusive. A novel postmitotic role for the APC/C at Drosophila neuromuscular synapses is described: independent regulation of synaptic growth and synaptic transmission. In neurons, the APC/C controls synaptic size via a downstream effector Liprin-alpha; in muscles, the APC/C regulates synaptic transmission, controlling the concentration of a postsynaptic glutamate receptor (van Roessel, 2004).
This study shows that the APC/C, a ubiquitin ligase known for its role in regulating cell cycle progression, functions in differentiated neurons to regulate synaptic growth, and in muscles to regulate synaptic transmission. The presence of the APC/C subunits Cdc27, Cdh1/Fizzy related, and APC2/Morula at synaptic structures, together with the accumulation of potential target proteins at synapses in APC2/mr mutants, suggest that the APC/C functions at synapses to regulate local ubiquitin-mediated protein degradation (van Roessel, 2004).
In neurons, the APC/C functions upstream of Liprin-α to constrain the number of synaptic boutons. Liprin-α interacts directly with Dlar, a protein tyrosine phosphatase, suggesting that the APC/C may modulate tyrosine phosphorylation at the synapse by negatively regulating Liprin-α levels. Genetic epistasis demonstrates that the APC/C requires Liprin-α to regulate synaptic bouton number. The regulation of Liprin-α by the APC/C may be indirect. However, the presence of three conserved destruction box motifs in Liprin-α, its accumulation following the loss of APC/C function in neurons, and the fact that Liprin-α is ubiquitylated in the nervous system in vivo, all suggest that it is a direct substrate of the APC/C. APC/C-dependent degradation of bacterially expressed Drosophila Liprin-α was sought in a Xenopus oocyte extract, but with little success. This could reflect the heterologous nature of the assay, or may indicate the requirement for a cofactor not present in Xenopus oocytes, as has been the case for other substrates of the APC/C (van Roessel, 2004).
The APC/C may regulate multiple proteins in differentiated neurons or muscle, just as it targets numerous substrates during the cell cycle. Indeed, other proteins degraded at the NMJ synapse, including Drosophila Unc-13, have putative destruction box sequence motifs. Interestingly, a role has previously been demonstrated for some cell cycle proteins at the Drosophila neuromuscular junction. For example a regulator of DNA replication, Latheo/ORC3, has been shown to affect synaptic function and behavior. Licensing of DNA replication is regulated during the cell cycle in part by the APC/C (van Roessel, 2004).
In muscles, the APC/C modulates muscle sensitivity to neurotransmitter and regulates the levels of a postsynaptic glutamate receptor. The upregulation of GluRIIa observed in APC2/mr mutants could result from: (1) an increase in local glutamate receptor synthesis, (2) inhibition of receptor turnover/degradation, or (3) an increase in glutamate receptor clustering at the synapse. In C. elegans, the glutamate receptor GLR-1 is ubiquitylated, and mutations that disrupt ubiquitylation led to increased accumulation of GLR-1 at central synapses. Although both GLR-1 and Drosophila GluRIIa each have a conserved destruction box motif, these lie in their extracellular domains, suggesting that glutamate receptors may not be direct targets of the APC/C. An alternative is that postsynaptic APC/C also functions through Liprin-α. In vertebrates, Liprin-α has a role in clustering glutamate receptors. Liprin-α mutations do not affect quantal size at the Drosophila NMJ, however, suggesting that Liprin-α is not necessary for regulating glutamate receptor levels in flies (van Roessel, 2004).
Recent evidence indicates that proteasome-mediated protein degradation regulates synaptic function in both vertebrates and invertebrates, although the molecular mechanisms for such regulation have been elusive. The putative ubiquitin ligase Highwire has been proposed to be a general regulator of the morphology and function of neuromuscular synapses in Drosophila. The physiological phenotypes of APC2/morula and highwire mutations, however, are dramatically different, indicating that ubiquitylation at the NMJ involves multiple ubiquitin ligase activities. Indeed there may be independent roles for regulatory monoubiquitylation and polyubiquitylation at Drosophila NMJs. A recent report has also described an acute requirement for ubiquitin-mediated proteolysis in regulating synaptic transmission at the Drosophila NMJ (Speese, 2003). Acute pharmacologic inhibition of the proteasome rapidly increases synaptic transmission, but does so via presynaptic mechanisms that increase transmitter release. Whether this role for ubiquitylation involves the APC/C or another ligase mechanism is unclear (van Roessel, 2004).
A role for protein degradation in regulating synaptic plasticity in Aplysia has been demonstrated. Longer term pharmacological inhibition of the proteasome facilitates serotonin-evoked synaptic strengthening at a central sensory-motor synapse. Presynaptic proteasome inhibition promotes growth of synaptic contacts, while postsynaptic inhibition increases the strength of glutamatergic synaptic inputs. Here, mutation of APC2/mr in Drosophila is sufficient to parallel both the pre- and post-synaptic effects of general proteasome inhibition at a central synapse in Aplysia. This leads to a suggestion that protein degradation via the APC/C may be an evolutionarily conserved mechanism for modulating synaptic strength. The APC/C may be a principal regulator of proteasome-dependent protein degradation at glutamatergic synapses, and thus a key effector of synaptic plasticity (van Roessel, 2004).
To understand the basis of the lethal and sterile phenotypes in mr mutants, the five mr mutations were sequenced. The mr3 mutant has the most severe phenotype in larval brains, and the molecular analysis confirms that this is the strongest allele. The mr3 strain contains a nucleotide substitution that is predicted to change Trp-282 to a stop codon, truncating the protein to approximately one-third of its length and removing the cullin domain. The mr4 and mr5 alleles were phenotypically characterized as strong alleles because they cause lethality, and these too have pronounced molecular changes. Both alleles share the same nucleotide substitution that would alter a splice acceptor site after the sixth intron. If the intron were not spliced, the protein would be expected to be missing the C terminus, including part of the cullin domain. The mr4 and mr5 were recovered from the same ethyl methanesulfonate screen and likely represent repeat isolates from the same premeiotic mutation event. The mr1 and mr2 alleles were isolated from natural populations about 20 years apart, and thus could contain the same mutation. Indeed, both have a single nucleotide change predicted to cause a Trp to Arg amino acid substitution. This change is C-terminal to the cullin domain. This Trp is conserved in mammalian APC2 subunits, but not in the budding yeast protein. This flexibility in amino acid sequence may explain why these are the weakest of the mr mutations (Kashevsky, 2002).
The identification of Morula as the APC2 component of the anaphase promoting complex readily explains the metaphase arrest observed in proliferating tissues from mr mutants and establishes that APC2 is essential for APC/C activity. This identification is significant also for demonstrating that the APC/C is necessary during endo cycles to inhibit mitotic functions and is consistent with the previous observation that levels of cyclin B are inappropriately high in mr mutant nurse cells (Reed, 1997). The finding that APC/C is required for endo cycles raised the question of whether increased levels of cyclin B were responsible, at least in part, for the larval mr mutant phenotypes. To address this question, whether increased levels of cyclin B could enhance mr phenotypes was examined. The transheterozygous combination of the mr1/mr3 mutant alleles provided a sensitized test because these transheterozygotes produce viable adults, though at only 50% the number predicted for a fully viable combination. The copy number of wild-type cyclin B genes was increased by two, thereby increasing the level of cyclin B protein. Increased cyclin B enhances the lethal phenotype such that in the presence of extra copies of the cyclin B gene, no viable mr1/mr3 adults were recovered. These results provide in vivo confirmation that levels of cyclin B affect the mr phenotype and contribute to the lethality of strong mr mutants (Kashevsky, 2002).
Tests were also performed for enhancement of the female-sterile phenotype of the mr1/mr2 alleles by increased levels of cyclin B to examine the requirements for APC/C function during specific differentiation aspects of the nurse cell endo cycle. The five initial endo cycles of the nurse cells produce polytene chromosomes in which the replicated sister chromatids remain in tight association. After cycle 5, the chromosomes condense, and then the replicated copies partially disperse so that in subsequent endo cycles the chromosomes appear polyploid rather than polytene. A striking feature of the mr1/mr2 phenotype is that the first five nurse cell endo cycles appear normal. The mr defect is not manifested until the polytene/polyploid transition, when in mr mutant nurse cells the chromosomes condense more fully than in wild type; spindles are formed, and the condensed chromosomes remain arrested in a metaphase-like state. This phenotype shows the same time of onset in nurse cells mutant for the lethal mr5 mutation, generated by germline clones. This finding raises the possibility that the polyteny/polyploidy transition involves a cell cycle change to a transient mitotic state and that, at this point, mr mutant nurse cells are vulnerable to reenter mitosis fully (Kashevsky, 2002).
Consistent with the proposal that the onset of the mr phenotype reflects cell cycle changes in the nurse cells at the polytene/polyploid transition, it was found that increased levels of cyclin B protein do not cause an earlier appearance of mitosis in the mr mutant nurse cells. No increase in the number of later stage egg chambers with pycnotic or degenerating nurse cells is observed in the presence of increased cyclin B. Elevation of cyclin B protein in a wild-type background is insufficient to cause nurse cells to revert to mitosis. It remains possible that increasing the levels of other APC/C substrates would cause an earlier endo cycle defect (Kashevsky, 2002).
The levels of mr transcript during egg chamber development were examined by in situ hybridization; the transcript is present in the nurse cells throughout oogenesis. There was not a detectable induction of mr transcript at the polyteny-polyploidy transition, as expected, given that APC/C activity is controlled posttranscriptionally. The mr transcript levels are increased in stage-10 egg chambers, a time when nurse cells undergo maximal gene expression (Kashevsky, 2002).
The mr mutants permitted an analysis of the requirements for APC/C function in two other variant cell cycles, meiosis and the embryonic S-M cycles. Although many egg chambers degenerate in the female-sterile mr1 and mr2 alleles after stage 7 because of attempted mitosis in the nurse cells, some egg chambers complete oogenesis. This number is affected by genetic background (Reed, 1997). In embryos produced by mr1/mr2 mutant mothers, the zygotic nuclei arrest in metaphase. Mature oocytes and embryos from these mothers were examined in more detail to determine whether meiosis is completed, whether pronuclear fusion occurs, and whether spindle structure is affected. Mature Drosophila oocytes are arrested in metaphase I, and the metaphase I arrest is properly maintained in all of the mature oocytes examined from mr1/mr2 mutant females. Embryos were examined to test whether meiosis is completed in mr1/mr2 mutants. Thirty-three embryos from mr1/mr2 mutant females that had been stained with antibodies against tubulin and a DNA stain were analyzed by confocal microscopy. Meiosis was completed in all of these embryos. There was not a meiosis I or a meiosis II spindle present, and this can be readily seen in mutants blocked in the meiotic divisions (Kashevsky, 2002).
Although meiosis is completed in these mr mutants, two striking features are that all of the zygotic nuclei, and frequently the polar bodies, are arrested on metaphase spindles that are anastral and have broad poles. An additional phenotype is that the chromosomes are hypercondensed in the embryos from mr mutant mothers. This phenotype was observed previously in metaphase-arrested neuroblasts, cells that are undergoing the canonical cell cycle (Reed, 1997). The excessive condensation seen in metaphase-arrested embryonic nuclei indicates that during the S-M cycles as well as the normal cell cycle the chromosomes continue to undergo condensation if they remain arrested in metaphase. To determine whether these phenotypes are the consequence of increased levels of cyclin B protein, attempts were made to phenocopy these affects by increasing cyclin B levels using strains with four extra copies of the cyclin B gene in a wild-type background. Embryos produced from these mothers does not exhibit the mr phenotypes. These observations complement the demonstration that increasing levels of cyclin B protein do not cause centrosomes to dissociate from the mitotic spindles. Increased levels of cyclin B do not worsen phenotypes in embryos from mr1/mr2 mutant mothers, suggesting these defects may be caused by increased levels of other APC/C targets (Kashevsky, 2002).
In the endo cell cycle, rounds of DNA replication occur in the absence of mitosis, giving rise to polyploid or polytene cells. The Drosophila morula gene is essential to maintain the absence of mitosis during the endo cycle. During oogenesis in wild-type Drosophila, nurse cells become polyploid and do not contain cyclin B protein. Nurse cells in female-sterile alleles of morula begin to become polyploid but revert to a mitotic-like state, condensing the chromosomes and forming spindles. In strong, larval lethal alleles of morula, the polytene ring gland cells also inappropriately regress into mitosis and form spindles. In addition to its role in the endo cycle, morula function is necessary for dividing cells to exit mitosis. Embryonic S-M cycles and the archetypal (G1-S-G2-M) cell cycle are both arrested in metaphase in different morula mutants. These phenotypes suggest that morula acts to block mitosis-promoting activity in both the endo cycle and at the metaphase/anaphase transition of the mitotic cycle. Consistent with this, cyclin B protein was found to be inappropriately present in morula mutant nurse cells. Thus morula serves a dual function as a cell cycle regulator that promotes exit from mitosis and maintains the absence of mitosis during the endo cycle, possibly by activating the cyclin destruction machinery (Reed, 1997).
Because mitosis occurs inappropriately in the polyploid nurse cells of mr mutant ovaries, whether morula function is required for proper mitosis in the early embryonic divisions was investigated. These nuclear divisions take place in a syncytial cytoplasm. They are controlled by maternal pools deposited during oogenesis and occur in a S-M cycle lacking gap phases. Although mr1 and mr2 females are always fully sterile, it is possible to recover stocks in which the oogenesis defect is suppressed, enabling the mutant females to lay eggs that do not hatch. In these stocks, the oogenesis defect is suppressed, but the morula visible phenotypes are still present and defects are observed in the early embryonic cycles that result from the morula mutations (Reed, 1997).
Eggs laid by homozygous mr2 or trans-heterozygous mr1/mr2 females were examined and early syncytial nuclei arrested in metaphase were observed. The embryos usually contained between six and ten metaphase nuclei, although occasionally up to 30 were present. The chromosomes were aligned on a metaphase plate and the spindles stained more intensely than wild type with anti-tubulin antibodies, possibly reflecting a greater density of microtubules. In addition, the spindles were broader than wild type both at the metaphase plate and at the spindle poles. Thus, in eggs from morula mutant mothers, only a few divisions appear to occur followed by metaphase arrest (Reed, 1997).
Normally the three unused meiotic products from the oocyte fuse into one or two rosette structures of condensed chromosomes surrounded by a sphere of tubulin. In the fertilized embryos from mr females, no normal polar bodies were observed, but metaphase spindles were consistently found at the position on the dorsal surface of the embryo normally occupied by the polar bodies. In unfertilized eggs from wildtype mothers, meiosis is completed and the meiotic products form rosette structures. In unfertilized eggs from mr mutants, between one and four metaphase figures were present rather than the rosette structure typical of polar bodies. In some cases, the chromosomes did not appear to be as tightly aligned on the metaphase plate as in the spindles present in fertilized mutant embryos. It is possible either that meiosis is not completed properly, arresting in meiotic metaphase, or that the polar bodies inappropriately assemble mitotic spindles in mr mutant eggs (Reed, 1997).
The observations that mr mutations produce a mitotic-like state in the polyploid nurse cells, arrest the early nuclear divisions in metaphase and appear to cause a metaphase spindle in the polar bodies, led to an examination of whether mr affects mitosis later in development in cells undergoing an archetypic G1-S-G2-M cell cycle. Both mr1 and mr2 are semilethal over non-complementing deficiencies, suggesting a general role for mr in cell cycle control. Escapers have etched tergites and very rough eyes, while most Df/mr1 or Df/mr2 heterozygotes die as pupae in the pharate adult stage. From this more severe phenotype, it can be assumed that mr1 and mr2 are not null alleles and that they are possibly hypomorphic (Reed, 1997).
Assuming that a null allele of morula could be selected as a lethal mutation, an EMS mutagenesis screen was performed; lethal mutations in the morula region (60A7-16) were selected. Three lethal alleles were recovered that fail to complement morula, here referred to as mr3, mr4 and mr5. The mr3 chromosome proved to carry a second, closely linked, lethal mutation and was not used for phenotypic analysis. The phenotype of these lethal alleles of morula conforms to what is now recognized as a mitotic cell cycle phenotype, the diagnostic features of which include late larval/early pupal lethality, small and poorly developed imaginal discs, and anomalous mitotic chromosome behavior as seen in larval brain neuroblast squashes. The lethal morula larvae often die as small third instar larvae. They may pupariate, but do not show a prolonged larval life. It is possible that the morula larvae that die in the third instar or as early pupae are escapers that receive a critical amount of wild-type maternal product and are able to successfully complete the embryonic divisions. It was found, however, that there is no embryonic lethality associated with the lethal morula alleles. This observation, together with the defects seen during the early nuclear divisions in eggs laid by mr1 or mr2 mutant mothers, indicates that there are maternal pools of morula product during early developmental stages (Reed, 1997).
All homozygous and heterozygous combinations of lethal morula alleles show anomalous mitotic chromosome behavior as evidenced by a metaphase block, highly overcondensed chromosomes and frequent polyploid figures in squash preparations of larval brain neuroblasts. Anaphase figures are never observed in the lethal morula combinations, thus the primary arrest point appears to be metaphase. The presence of polyploid cells is not inconsistent with metaphase arrest, since several other late larval mutants contain both metaphase-arrested and polyploid cells. It is likely that metaphase-arrested cells are capable of reverting to interphase and undergoing DNA replication. Because the chromosomes of the blocked metaphases are frequently hypercondensed, it is often difficult to determine if sister chromatids remained attached or if they dissociate. As a consequence it is not possible to determine accurately the ploidy level of these nuclei. With this proviso in mind, metaphase figures are most frequently tetraploid or octaploid. Ploidy values higher than octaploid are not frequent. Many nuclei appear pycnotic. Confocal microscopy of anti-tubulin-gamma and DNA-stained mutant larval brains confirmed a metaphase arrest phenotype (Reed, 1997).
In addition to the aspects of the mutant phenotype typical of mitotic mutants, the lethal morula phenotype also displays necrosis of the gut just caudal to the attachment of the Malpighian tubules. The site of the necrosis, which often appears as a dark ring visible through the larval cuticle, corresponds to the location of the hindgut imaginal ring and may reflect cell death resulting from mitotic defects. However, other imaginal rings (foregut, salivary gland) examined in mutant larvae did not appear necrotic (Reed, 1997).
In morula mutants, there is an aberrant mitotic state in the endo cycle and a failure to exit mitosis during division. The inactivation of cdc2/cyclin B kinase normally is required for the completion of mitosis and the kinase is likely to be inactive during the endo cycle. Therefore one possible explanation for the observed morula phenotypes is that morula plays a role in the inactivation or the maintenance of the inactivation of the cdc2/cyclin B kinase (Reed, 1997).
Cdc2/cyclin B kinase is inactivated during mitosis by cyclin B degradation. Cyclin B protein is absent in the polyploid nurse cells, even though the transcript is present in early egg chamber stages. To test whether morula can destabilize cyclin B, cyclin B protein levels were examined in morula mutant ovaries. Anti-cyclin B staining in ovaries from mr2 females and wild-type siblings (stained in the same Eppendorf tube) were compared. In the wild-type nurse cells, cyclin B protein is absent or present at levels only slightly above background. In contrast, in mr2 mutant nurse cells, cyclin B protein is readily detectable. Dividing follicle cells of both wild-type and mutant egg chambers show a patchwork staining pattern reflecting local synchrony of mitotic divisions. In this experiment, the intensity of the follicle cell staining serves as an internal reference. Comparing the cytoplasmic staining in the nurse cells to the patchwork pattern of the follicle cells, it can be observed that the nurse cell staining of mr2 nurse cells matches the bright follicle cell staining. In contrast, the nurse cells of the sibling control more closely resemble the weakly staining follicle cells. Thus, in mr mutant nurse cells, cyclin B protein is present at inappropriately high levels, suggesting that cdc2 kinase activity is also high. Because the follicle cells are actively dividing during the relevant stages of oogenesis, it was not possible to directly assay nurse cell kinase activity in ovary extracts (Reed, 1997).
If high cyclin B levels and associated cdc2 kinase activity disrupt the endo cycle by inducing mitotic functions in morula mutants, then cdc2 activity must normally not be required during polyploidization of the nurse cells. The endo cell cycle of the larval polytene cells does not require cdc2 activity. Tests were performed to see whether nurse cell development normally requires cdc2 by using a temperature-sensitive allele to eliminate activity during oogenesis. By crossing a temperature-sensitive mutation cdc2 mutant to a null mutant, adult females were recovered that cease to lay eggs at the restrictive temperature. Upon shifting to restrictive temperature, dividing cells in the ovary gradually disappear over a period of 5 days. In contrast, nurse cell nuclei persist. Since the overall size of nurse cell nuclei increases with time spent at restrictive temperature, the temperature shift does not arrest nurse cell growth. Using nurse cell growth to indicate endo cell cycle activity, it is concluded that wild-type nurse cell endo cycles do not require cdc2. This is consistent with the proposal that the inappropriate mitotic state in morula nurse cells results from misregulation of cdc2/cyclin B kinase (Reed, 1997).
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date revised: 10 April 2013
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