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I acknowledge the Traditional Owners of the land on which I live, who are a part of the Kulin nation. I pay my respects to their Elders, past, present and emerging, and the Aboriginal Elders of other communities who may be here today.

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Although previous reports suggested that carbonated water drinking was effective against gastrointestinal symptoms, there is little information about the effects of carbonated water on gastric and appetite sensation. We therefore investigated the effect of carbonated water on short-term fullness with respect to gastric and cardiac responses in 19 healthy young women. Each subject was tested on three separate days at approximately 9 a.m. after an overnight fast. Gastric motility, evaluated by electrogastrography (EGG) and heart rate (HR), was measured for 20 min in the fasting state and 40 min after ingestion of water. Preloads consisted of an equivalent amount (250 mL) of water (W) or carbonated water (CW) and no drinking (blank). Fullness scores were measured using visual analog scales. To determine gastric motility, we assessed the component of bradygastria (1-2 cycles/min [cpm]), normogastria (2-4 cpm), tachygastria (4-9 cpm), and dominant frequency of the EGG power spectrum. After ingestion of CW, significant increases in fullness scores were observed compared with W. All postprandial EGG powers were significantly greater than preprandial, but no group difference was found. However, a dominant frequency tended to shift toward a lower band after ingestion of W. A significantly higher HR was found following consumption of CW as opposed to W. Multiple regression analysis revealed that increased HR was a significant variable contributing to the variances in fullness after ingestion of CW at 40 min. Our data suggest that CW may induce a short-term, but significant, satiating effect through enhanced postprandial gastric and cardiac activities due possibly to the increased sympathetic activity and/or withdrawal of parasympathetic activity.

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Consumption of sugar sweetened beverages exhibits strong associations with weight gain, obesity, and dental caries, especially in young children. The aim of this article is to estimate price elasticities for parents' sugar-sweetened beverages consumption choices with respect to their pre-school children and to estimate elasticities with respect to nutritional attribute labels across sugar-sweetened beverages. Our results show that 1% increase in the price of fizzy drink, juice and cordial would reduce pre-school children's consumption of each drink by 0.80%, 0.51%, and 0.34% respectively. Such price effects on children's consumption do not substantially differ between high and low-income respondents but the effect on the children's Fizzy Drink consumption is significantly larger for respondents from large households than those from small households and are significantly lower than the price effects on the consumption of the rest of the family for Juice and Cordial. The marginal effects of demand with respect to nutritional attribute labels of sugar-sweetened beverages matter for Juice and Cordial, and are strongest for low-income families; however, these effects do not substantially differ between large and small-household respondents.

N2 - Consumption of sugar sweetened beverages exhibits strong associations with weight gain, obesity, and dental caries, especially in young children. The aim of this article is to estimate price elasticities for parents' sugar-sweetened beverages consumption choices with respect to their pre-school children and to estimate elasticities with respect to nutritional attribute labels across sugar-sweetened beverages. Our results show that 1% increase in the price of fizzy drink, juice and cordial would reduce pre-school children's consumption of each drink by 0.80%, 0.51%, and 0.34% respectively. Such price effects on children's consumption do not substantially differ between high and low-income respondents but the effect on the children's Fizzy Drink consumption is significantly larger for respondents from large households than those from small households and are significantly lower than the price effects on the consumption of the rest of the family for Juice and Cordial. The marginal effects of demand with respect to nutritional attribute labels of sugar-sweetened beverages matter for Juice and Cordial, and are strongest for low-income families; however, these effects do not substantially differ between large and small-household respondents.

AB - Consumption of sugar sweetened beverages exhibits strong associations with weight gain, obesity, and dental caries, especially in young children. The aim of this article is to estimate price elasticities for parents' sugar-sweetened beverages consumption choices with respect to their pre-school children and to estimate elasticities with respect to nutritional attribute labels across sugar-sweetened beverages. Our results show that 1% increase in the price of fizzy drink, juice and cordial would reduce pre-school children's consumption of each drink by 0.80%, 0.51%, and 0.34% respectively. Such price effects on children's consumption do not substantially differ between high and low-income respondents but the effect on the children's Fizzy Drink consumption is significantly larger for respondents from large households than those from small households and are significantly lower than the price effects on the consumption of the rest of the family for Juice and Cordial. The marginal effects of demand with respect to nutritional attribute labels of sugar-sweetened beverages matter for Juice and Cordial, and are strongest for low-income families; however, these effects do not substantially differ between large and small-household respondents.

Embryonic To examine the distribution of Fzy protein during developmentand mitosis mouse monoclonal antibodies were generated against a Fzy fusion protein. One of these antibodies,mAb 20.B.9, recognizes a single protein of ~59 kD on Westernblots of Drosophila embryonic extracts. This is in agreement with the expected molecular massof 59 kD for Fzy predicted by sequence analysis. To demonstratethat this 59-kD band is indeed Fzy protein, mAb 20.B.9 was used to probe a Western blot of extracts from yeastcells, which either carded or did not carry the fzy expressionconstruct. This antibody detects a 59-kD band in the extractfrom the cells containing the fzy expression construct butnothing in the control extract from untransformed yeast, demonstrating both that the 59-kD band seen on Western blots is Fzy and the specificity of the mAb 20.B.9 antibody for Fzy (Dawson, 1995).To test the specificity of this antibody for use in wholemount staining of embryos the staining of embryoshomozygous for Df(2L)H60-3, which completely removesthe fzy coding sequence, was compared with their phenotypicaUywild-type sibs. Up to stage 10 mAb 20.B.9 shows homogeneousstaining of all embryos in the population regardless oftheir genotype. Failure to detect obvious differences in staining patterns between wild-type and homozygous Df(2L)H60-3 embryos up to this point is not unexpected as genetic evidence indicates that maternally suppliedfzy+ product perdures until approximately this stage. However, by stage 14, when Df(2L)H60-3 embryos can be unambiguouslyidentified morphologically by their fzy- phenotypeand the maternally supplied product has beendepleted, phenotypically wild-type embryos show specificstaining that is absent in their mutant sibs (Dawson, 1995).Having confirmed the specificity of mAb 20.B.9 for Fzy, it was used to examine the distribution of Fzy protein duringembryonic development. In newly fertilized eggs andvery early embryos maternally supplied fzy appears to berelatively homogeneously distributed throughout the embryo. As the nuclear density increases duringstage 2 fzy staining becomes more pronounced in the energids,the cytoplasmic islands associated with the nuclei, thanin the surrounding yolk. By stage 5 when themajority of nuclei have migrated to the embryonic peripheryand cellularization is occurring most of the Fzy staining isalso present in the cortical cytoplasm at the embryonic periphery.There is no Fzy staining associated with the vitellophagesthat remain in the yolk; the vitellophagesdo not divide again. These differences in Fzy stainingduring early development presumably reflect changes inthe distribution of maternally supplied protein as they occurbefore high levels of zygotic transcription occur. From stage 5 to 10 Fzy is uniformly expressedthroughout the cellular regions of the embryo. During these stages Fzy is also present in cells of theamnioserosa, which do not undergo further division, which presumably reflects the perdurance of maternallysupplied protein. Only fairly late inembryogenesis, from stage 11 onwards, do noticeable differencesin intensity offzy staining become apparent.These changes appear to correlate with cell division patterns:in tissues where cell division is ceasing, such as theepidermis and mesoderm, Fzy staining gradually declines,whereas in the remaining actively dividing tissues such asthe neuroblasts and ganglion mother cells of the central nervoussystem (CNS) Fzy is still expressed strongly. This correlationbetween continued high Fzy expression and mitotic activityis most marked in later stages where Fzy is expressedexclusively in the few remaining actively dividing cells, theneuroblasts and ganglion mother cells of the CNS (Dawson, 1995).The subcellular distribution of Fzy was examined duringmitosis. The nuclear divisions of the precellular blastodermstage embryos, because of their synchrony and the superficialand single-layered arrangement of nuclei are theeasiest to examine. In interphase of these divisions, beforeentry into mitosis, Fzy is primarily or exclusively cytoplasmic. While some weak nuclear staining is seen thisis much less intense than the cytoplasmic staining and it is not certain whether this represents background fromthe detection methods used or whether this accuratelyreflects the distribution of Fzy protein. During prophase Fzyremains primarily cytoplasmic but the level of nuclear stainingincreases; in addition, the boundary between nuclearand cytoplasmic staining becomes much less distinct. By prometaphase/metaphase Fzy staining is ubiquitous,though the intensity of staining is significantly less in the regionoccupied by the chromosomes themselves than in theadjacent areas. During anaphase, the exclusion ofFzy from the region occupied by the DNA becomes morepronounced and by telophase, as the nuclear envelopeis reformed, Fzy staining once again becomes cytoplasmic. This same alteration in Fzy distribution duringmitosis, i.e., from cytoplasmic to ubiquitous, except over the DNA itself, to cytoplasmic again, also occurs during the later cellular divisions with the same timing relative to mitotic progression (Dawson, 1995). Effects of Mutation or DeletionMutations of the tag_hash_116_____ locus cause metaphase arrest in Drosophila embryosMutations in the fizzy gene of Drosophila cause cells in mitosis to arrest at metaphase. Maternally supplied fizzy activity is required for normal nuclear division in the preblastoderm embryo and, during later embryogenesis, zygotic fizzy activity is required for the development of the ventrally derived epidermis and the central and peripheral nervous systems. In fizzy embryos, dividing cells in these tissues arrest at metaphase, fail to differentiate and ultimately die. In the ventral epidermis, if cells are prevented from entering mitosis by using a string mutation, cell death is prevented and the ability to differentiate ventral epidermis is restored in fizzy; string double mutant embryos. These results demonstrate that fizzy is a cell cycle mutation and that the normal function of the fizzy gene is required for dividing cells to exit metaphase and complete mitosis (Dawson, 1993; full text of article). Exit from mitosis is regulated by Drosophila fizzy and the sequential destruction of cyclins A, B and B3While entry into mitosis is triggered by activation of cdc2 kinase, exit from mitosis requires inactivation of this kinase. Inactivation results from proteolytic degradation of the regulatory cyclin subunits during mitosis. At least three different cyclin types, cyclins A, B and B3, associate with cdc2 kinase in higher eukaryotes and are sequentially degraded in mitosis. Mutations in the Drosophila gene fizzy block the mitotic degradation of these cyclins. Moreover, expression of mutant cyclins ( cyclins) lacking the destruction box motif required for mitotic degradation affects mitotic progression at distinct stages. cyclin A results in a delay in metaphase, cyclin B in an early anaphase arrest and deltacyclin B3 in a late anaphase arrest, suggesting that mitotic progression beyond metaphase is ordered by the sequential degradation of these different cyclins. Coexpression of cyclins A, B and B3 allows a delayed separation of sister chromosomes, but interferes with chromosome segregation to the poles. Mutations in fzy block both sister chromosome separation and segregation, indicating that fzy plays a crucial role in the metaphase/anaphase transition (Sigrist, 1995; full text of article).tag_hash_128_____ is required for normal degradation of cyclins A and B during mitosis The Drosophila cell cycle gene fizzy (fzy) is required for normal execution of the metaphase-anaphase transition. fzy has been cloned, and this has been confirmed by P-element mediated germline transformation rescue. Sequence analysis predicts that fzy encodes a protein of 526 amino acids, the carboxy half of which has significant homology to the Saccharomyces cerevisiae cell cycle gene CDC20. A monoclonal antibody against Fzy detects a single protein of the expected size, 59 kD, in embryonic extracts. In early embryos fzy is expressed in all proliferating tissues; in late embryos fzy expression declines in a tissue-specific manner correlated with cessation of cell division. During interphase fzy protein is present in the cytoplasm; while in mitosis fzy becomes ubiquitously distributed throughout the cell except for the area occupied by the chromosomes. The metaphase arrest phenotype caused by fzy mutations is associated with failure to degrade both mitotic cyclins A and B, and an enrichment of spindle microtubules at the expense of astral microtubules. These data suggest that fzy function is required for normal cell cycle-regulated proteolysis that is necessary for successful progress through mitosis (Dawson, 1995).During the cellular mitoses of wild-type embryos Cyclin Adegradation occurs during metaphase whereas Cyclin Bdegradation occurs at the metaphase-anaphase transition. Polyclonal antisera specific for either cyclin A or cyclin B was used to assaycyclin degradation in fzy- embryos. In the dorsalepidermal region of wild-type embryos by stage 14 mostcells have ceased dividing and consequently few cells stainpositively for either cyclin A or B. In contrast,in the same region of stage 14 fzy- embryos manymore cyclin A and cyclin B positive cells are present andmany of these cells contain metaphase figures. In fzy- embryos the peripheralnervous system (PNS) precursors underlying thedorsal epidermis arrest in metaphase (Dawson, 1993).Based on this observation, the pattern and the subepidermalposition of the cyclin positive cells in the dorsal epidermalregion of the fzy- embryos it is concluded that these aremetaphase-arrested PNS precursors. Similar results wereobserved in the metaphase-arrested cells of the cephalic andventral epidermis of fzy- embryos. Higher magnificationviews of such metaphase-arrested cells in the epidermis ofmutant embryos show almost all stain positively for cyclin Aand most stain positively for cyclin B. Thus the metaphase arrest phenotype caused by fzy- mutations is usually accompanied by failure to degrade both mitotic cyclins A and B (Dawson, 1995).Since CDC20 has been proposed to regulate microtubulebehavior (Sethi, 1991), the effects oftreatment with either colchicine, a microtubule-destabilizingagent, or taxol, a microtubule-stabilizing drug, were examined on mitoticcyclin degradation during the postblastoderm divisions ofDrosophila embryos. Treatment with either drug results ina pseudometaphase arrest in which many mitotic cells withcondensed chromatin are present but no anaphase or telophasefigures are seen. During the postblastoderm divisionscolchicine-treated pseudometaphase-arrested cellsdegrade cyclin A but not cyclin B. Taxol hasa similar effect on mitotic cyclin degradation as colchicine,specifically taxol-treated pseudometaphase-arrested cellsare readily able to degrade cyclin A but donot degrade cyclin B (Dawson, 1995).One of the phenotypes of the cdc20-1 mutation of buddingyeast is an increase in the amount of tubulin incorporatedinto spindle microtubules when cdc20-1 cells are arrested inmitosis at the restrictive temperature (Sethi, 1991). An anti-tubulin antibody was used to examine spindle morphologyin embryos from fzy mutant mothers, fzy minus embryos.Such fzy mutant embryos lack sufficient maternally supplied fzyproduct, do not develop beyond the 2nd or 3rd nuclear divisionand their nuclei arrest at the metaphase-anaphase transition(Dawson, 1993). Most of the spindles of themetaphase arrested nuclei in fzy minus embryos clearly containan excess of microtubules as compared with the spindles ofcontrol, wild-type embryos at the same stage of mitosis andin the same division cycle. In addition,whereas in control embryos astral microtubules as well asspindle microtubules can be seen to radiate out from the centrosomes, in the fzy minus embryos all the microtubulesemanating from the centrosomes are incorporated intothe spindle. Although most spindles in mutant embryosexhibit this excess of microtubules, the degree towhich this occurs if somewhat variable and there are occasionalspindles in mutant embryos that are indistinguishablefrom those of the wild-type controls. Similarly, in the ventralepidermis of fzy- embryos some metaphase-arrestedceils are seen that appear to contain excess spindle compared to thespindles of mitotic figures in the wild-type sibs present in thesame preparation, again the degree to which this occurs isquite variable (Dawson, 1995).Cort and Fzy are required for the completion of meiosis I and meiosis IIThe Drosophila genome contains four Cdc20/Cdh1 genes(Jacobs, 2002). Fzr2 appears to be exclusively transcribed in the male germline (Jacobs, 2002), whereas Cdh1 is transcribed in the female germline (Sigrist, 1997), but the protein is not detectable in early embryos, either by western blot analysis or by in vivo functional assays (Jacobs, 2002; Raff, 2002). To determine the role of APC complexes in female meiosis, focus was placed on the canonical Cdc20 (fzy), and a female-specific Cdc20/Cdh1 homologue, cort, both of which arehighly expressed in the female germline (Chu, 2001; Dawson, 1995). The meiotic phenotypes of cort and fzy mutants were re-examinedseparately and in double-mutant combinations by observing spindles and DNA,and by following chromosome segregation using FISH against an X-chromosomeprobe. Temperature-sensitive fzy mutants were analyzed at 29Cand, to control for temperature effects, wild-type and cort mutantswere therefore examined at both room temperature and at 29C. In femaleDrosophila, meiosis arrests in metaphase of the first meioticdivision until ovulation. At this stage, the egg contains a single spindle near the anterior cortex; this spindle contains two X-chromosome signals representing the two pairs of sister chromatids. Upon ovulation, meiosis resumes. In metaphase of meiosis II, two tandemly arranged spindles form around the products of the first meiotic division. Both metaphase spindles contain a single sister chromatid pair. In anaphaseII, sister chromatids separate, resulting in four meiotic products, each witha single X-chromosome. Meiosis is completed very rapidly after ovulationand, at 22C, only 1 of eggs from a 0-2-hour-oldcollection were still in meiosis. The remainder of eggs contained arrestedmeiotic products (polar bodies). Similarly, in eggs from females kept at29C, only 4% ) were in meiosis. In addition, 3% of eggscontained aberrant spindles near the cortex, suggesting low-level disruptionof meiosis at this temperature. As previously described, eggs fromcort-mutant females (hereafter referred to as cort eggs)contain two spindles near the anterior cortex of the egg, indicative of anarrest in meiosis II (Chu, 2001; Lieberfarb, 1996; Page, 1996). Similarly, at 29C, 90% of cort eggs contained two meiotic spindles. Both of the spindles contained a single X-chromosome signal, indicating an arrest in metaphase, prior to sister chromatid separation (Swan, 2007).Cks30A, like cort, is required for the proper completionof meiosis II, consistent with a model in which Cks promotes the activation of APCCort (Swan, 2005a). However, whereas cort mutants invariably arrest in the second meiosis, in Cks30 mutants, most oocytes eventually complete meiosis, although they are delayed in doing so(Swan, 2005a). In 0-2-hour-old collections of Cks30AKO eggs, 26% were in meiosis II. In 58% of these, both spindles had a singleX-chromosome signal and were therefore in metaphase of meiosis II, while theremaining 42% had two X-chromosomes per spindle and were therefore in anaphase of meiosis II. Therefore, loss of Cks30A results in ameiotic phenotype similar to, but weaker than, cort, suggesting thatCks30A activity enhances but is not essential for the function of theAPCCort (Swan, 2007).In Drosophila, as in most eukaryotes, Fzy is the crucial APCadaptor in mitosis, and is essential for anaphase progression in most celltypes (Dawson, 1993; Dawson, 1995; Sigrist, 1995). It is not yet known if Fzy is also required for anaphase progression in the meioticdivisions. To address this question, female meiosis were analyzed in eggsproduced by fzy females. fzy, unlike cort orCks30A, is essential for viability, and germline clones of a nullallele did not produce eggs. However, temperature-sensitiveallele combinations raised at a permissive temperature are viable and havebeen used to study the role of fzy in early embryogenesis(Dawson, 1995). fzy6/fzy7 mutants raised at the permissive temperature of 22C are female-sterile and embryos arrest in the first mitosis (Dawson, 1993). Meiosis appeared to be unaffected in these eggs. To achieve a stronger phenotype, fzy6/fzy7 females were shifted to the restrictivetemperature of 29C. In addition to the mitotic arrest, eggs fromfzy6/fzy7 females kept at 29C(hereafter referred to as fzy eggs) displayed defects in meiosis. 74% of fzy eggs contained two spindles near the cortex, indicative of adelay or arrest in meiosis II. In most cases, both spindles contained twoX-chromosome signals, indicating that sister chromatid separation hadoccurred and that they were therefore in anaphase of meiosis II. Often, thetwo X-chromosomes were not properly aligned along the spindle axis, probablyas a result of prolonged arrest. In rare cases, more than twoX-chromosome signals per spindle were detected, suggesting that DNAreplication can occur during the aberrant meiosis in fzy eggs. No meiotic spindles were observed with only a single X-chromosome, indicating that meiosis did not detectably delay or arrest in metaphase of meiosis II in these eggs. Eggs often contained, near the two major spindles, one or more smaller spindles with associated chromatin, possibly resultingfrom chromosome loss at the first meiotic division. In total, 13% of embryoscontained one or more spindles at the anterior cortex in addition to a polarbody, suggesting a partial completion of meiosis, whereas 6% of embryoscontained only polar bodies at the anterior cortex, and therefore appear tohave completed meiosis (Swan, 2007).In total, 8% of fzy eggs contained only a single spindle near thecortex, possibly indicative of a meiosis I arrest. The same percentage of eggsfrom cort mutants raised at 29C also arrested with a singlemeiotic spindle,suggesting the possibility that cort and fzy play partiallyredundant roles in meiosis I. To test this possibility, thephenotype was analyzed of a fzy; cort double mutant raised at 29C. In total,74% of fzy; cort double-mutant eggs contained twospindles, each with a single X-chromosome signal, indicatingthat they arrested in metaphase of the second meiotic division. The remaining26% of the eggs contained only a single spindle containing two X-chromosomesignals, indicating an arrest in meiosis I. It is concluded that the two APC adaptors Cort and Fzy are necessary for anaphase progression in both meiotic divisions, performing partially redundant roles in meiosis I and non-redundant roles in meiosis II (Swan, 2007).In addition to its role in anaphase, Cks30A is required earlier in meiosis, for the assembly or maintenance of the first meiotic spindle(Pearson, 2005; Swan, 2005). Todetermine whether spindle assembly or metaphase I arrest is affected incort or fzy mutants, chromosome alignment was analyzed inunactivated oocytes using the X-chromosome FISH probe. In metaphase I in wildtype, the autosomes are aligned at the spindle equator while the X-chromosomes are typically precociously segregated to either pole. Chromosomes were properly aligned in both cort and fzy mutants, as well as in fzy; cort double mutants. Therefore, with the caveat that it was not possible to study null alleles of cort and fzy, it is concluded that the first requirement for cort and fzy in meiosis is in anaphase of meiosis I (Swan, 2007).Cyclin destruction is necessary for the completion of meiosis in DrosophilaIn mitotic cells of most eukaryotes, the APCFzy promotesanaphase by targeting cyclins and other mitotic regulators for destruction(Peters, 2002). The importance of cyclin destruction in the two meiotic divisions is less clear. To determine whether cyclin destruction is necessary for female meiosis in Drosophila, meiotic progression was sexamined in eggs from females expressing a destruction-box (D-box) mutated form of cyclin B - cyclin B-TPM-GFP).When expressed in the female germline, cyclin B-TPM-GFP results in mitoticarrest at a variable stage of the syncytial mitotic cycle in the majority ofembryos, indicating that cyclin B destruction is necessary for anaphaseprogression in these cell cycles. To determine whether a failure to destroy cyclin B also disrupts meiosis, cyclin B-TMP-GFP was expressed with the strong germlinedriver nosGal4VP16 at 29C (to induce higher expression). Under theseconditions, almost all embryos arrested in the first mitotic division. In addition to this mitotic arrest, only 38% appeared to complete female meiosis, as judged by the presence of polar bodiesand the absence of spindles at the dorsal anterior of the egg. A total of 50%of eggs contained multiple small spindles in the dorsal anterior, possibly asa result of meiotic spindle breakdown and/or chromosome mis-segregation. Theremaining 14% of eggs appeared to arrest in meiosis. A small proportion of the eggs (4%) had two spindles with either one or two X-chromosomes, indicative of an arrest in either metaphase or anaphase of meiosis II. Inaddition, 10% of the eggs contained a single spindle at the dorsal anterior,typically with two X-chromosome signals, indicative of a meiosis I arrest. Therefore, cyclin B destruction is necessary for the proper completion of female meiosis in Drosophila (Swan, 2007).Cort and Fzy are required for the destruction of mitotic cyclins in the eggThe above results suggest the possibility that the meiotic arrest incort and fzy eggs could be caused by a failure to destroymitotic cyclins. In Drosophila, it is not known whether theAPCFzy has any role in cyclin destruction during meiosis. In contrast, the APCCort has been implicated with Cks30A incyclin A destruction in the female germline(Swan, 2005). Todetermine the respective roles of cort and fzy in cyclindestruction in female meiosis, cyclin levels were compared in egg extracts fromcort, fzy and Cks30A single mutants, and from fzy;cort double mutants. All of these mutants arrest at or before entry intothe first mitotic cell cyclem and therefore unfertilized, and thereforenon-cycling, wild-type eggs were used for control extracts. Cks30A and cort eggs contain high levels of cyclin A protein(Swan, 2005). Cyclin A levels werenot elevated in egg extracts from fzy mutants raised at 22C. However, eggs from fzy females kept at 29Cshowed a clear elevation in cyclin A levels, and fzy; cort doublemutants had an even-greater elevation in cyclin A levels. Therefore,fzy and cort are both required for cyclin A destruction inthe Drosophila egg. Cyclin B and cyclin B3 levels were also elevatedin fzy and cort single mutants, and more so in fzy;cort double mutants, indicating that Cort and Fzy cooperate in the destruction of all three mitotic cyclins. Comparing the relative effects of cort andfzy mutants on the different cyclins suggests that Cort is moreimportant for cyclin A and cyclin B3 destruction, whereas Fzy is moreimportant for cyclin B destruction. Therefore, the two APC adaptors may havedifferent target preferences (Swan, 2007).In Xenopus and mice, Cks2 is necessary for the activation of theAPCFzy complex by associating with Cdk1 and promoting itsphosphorylation of the APC subunits Cdc27 and Cdc16 (Patra, 1998;Spruck, 2003). In Drosophila, Cks30A interacts with Cdk1 in the germline and is required for cyclin A destruction (Swan, 2005a). Cks30A eggs also have elevated cyclin B3 levels, and both cyclin A and cyclin B3 were at levels higher than in cort or fzy single mutants, and were approaching levels observed in fzy; cort double mutants. This could be explained if Cks30A activity is required for the function of both APCFzy and APCCort complexes. Cyclin B, by contrast, is not strongly affected in Cks30A mutants, indicating that Cks30A plays a lesser role in promoting the activity of APCFzy and APCCort in cyclin B destruction (Swan, 2007).The above results indicate that Cort, like other Fzy/Cdh1-family proteins, functions in the targeting of mitotic cyclins for destruction. To further test the ability of Cort to target cyclins for destruction, HA-taggedCort was expressed in a stripe of cells in the wing imaginal disc using the Gal4-UAS system and then cyclin levels were examined by immunolocalization. The expression of HA-Cort resulted in a corresponding decrease in cyclin A, cyclin B and cyclin B3, consistent with these cyclins being targeted for destruction by Cort. A similar effect was observed upon the overexpression of Fzy or Cdh1. Therefore, Cort is able to target all of the mitotic cyclins for destruction,consistent with a proposed role as an APC adaptor (Swan, 2007).The reduction of cyclin levels would be expected to inhibit mitosis in the wing imaginal disc. Each cell in the wing secretes a single bristle, and mitotic failure results in fewer, but larger, cells; consequently, there are fewer wing hairs. Indeed, the expression of Fzy or HA-Cort in the posterior compartment of the wing disc, using the enGal4 driver, led to fewer but larger cells, as judged by an increase in the spacing between the wing hairs. To test the possibility that Cks30A is required for the activation of the APCCort, enGal4 was used to express HA-Cort in Drosophila that also lacked zygotic expression of Cks30A. In the Cks30A background, the wing-hair-spacing phenotype was suppressed. It was largely restored if Flag-Cks30A is coexpressed with HA-Cort in the Cks30A-mutant background, whereas the expression of Flag-Cks30A alone had no effect. Therefore, Cks30A is required for Cort activity (Swan, 2007).Cyclin B associates dynamically with the meiotic spindle

Cyclin B undergoes incomplete destruction in the syncytial mitotic cycles,apparently as a result of localized destruction restricted to spindles. It is not known how this local destruction is mediated, or whether localized cyclin B destruction is unique to the syncytial mitotic cycles or whether it alsooccurs in the preceding meiotic divisions. To determine if cyclin B is subjectto localized destruction in female meiosis, thelocalization of cyclin B was determined in wild-type meiosis. In Drosophila females,meiosis is arrested in metaphase of the first meiotic division until ovulationand cyclin B accumulates at high levels on the metaphase I spindle. Thiscyclin B accumulation is nonuniform and appears to be focused at the meioticspindle mid-zone - the region of the meiotic spindle where non-kinetochoremicrotubules from either pole overlap. The meiotic spindle mid-zone (ormeiotic metaphase central spindle) appears to play a specialized role inestablishing spindle bipolarity and in recruiting chromosomal passengerproteins to the meiotic spindle. To confirm that cyclin B associates with the spindle mid-zone, oocytes were double-labeled for both cyclin B and the spindle mid-zone component Subito (Sub). Cyclin B and Sub appeared to colocalize precisely, confirming thatcyclin B specifically associates with the spindle mid-zone in metaphase ofmeiosis I. In anaphase of meiosis I, the spindle mid-zone extends as thespindle elongates, and chromosomes segregate to either pole. Cyclin Bpersisted on the spindle mid-zone throughout anaphase I. Upon assembly ofthe second meiotic spindle, cyclin B appeared to redistribute to the spindlemid-zone of the newly formed meiosis II spindles. The protein persisted at the spindle mid-zone after the onset of anaphase, but was no longerdetected later in anaphase. Therefore, cyclin B is associated with the meiotic spindle mid-zone throughout meiosis, and dissociates from the spindle late in anaphase II. This pattern of accumulation suggests that cyclin B, presumably in complex with Cdk1, plays a unique role at the meiotic mid-zone in meiosis I and meiosis II, and that it is targeted for destruction at this site in anaphase II (Swan, 2007).Cort, Fzy and Cks30A are required for the local destruction of cyclin BTo determine if the dissociation of cyclin B from meiotic and mitoticspindles in anaphase reflects its local destruction by the APCCortor APCFzy, cyclin B distribution in wild-type eggs was compared with eggs fromcort and fzy single-mutant females at 29C. Incort, cyclin B accumulated on the arrested meiotic spindles. This accumulation was significantly higher thanthat detected in wild-type metaphase II, suggesting that cyclin B isstabilized on the arrested spindle. In cort, as in wild type, cyclinB specifically associated with the overlapping microtubules of the spindlemid-zone, co-localizing with the mid-zone component Sub. fzy eggsalso arrested, with elevated levels of cyclin B on the meiosis II spindles. However, rather thanexclusively accumulating at the spindle mid-zone, cyclin B was at lower levelsmore uniformly along the spindle. The finding that mutations in cortand fzy result in a stable association of cyclin B with the meioticspindle strongly supports a model in which the loss of cyclin B from themeiotic spindle in anaphase is a result of localized destruction by theAPCCort and APCFzy complexes (Swan, 2007).The difference in site of cyclin B accumulation on the meiotic spindlebetween cort and fzy could be a result of Cort and Fzyhaving distinct sites of activity. In this model, Cort would mediate cyclin Bdestruction at the spindle mid-zone while Fzy targeted cyclin B along thelength of the spindle. One consequence of this model would be that fzy;cort double mutants might have a cyclin B accumulation that is the sum ofthat of the two single mutants. Alternatively, Cort and Fzy may mediate cyclinB destruction at different stages of meiosis. In this model, Cort wouldmediate cyclin B destruction in metaphase when cyclin B is primarily at themid-zone, and Fzy would function in anaphase along the entire spindle. Thismodel fits with the time of arrest of cort and fzy inmetaphase and anaphase, respectively, and it predicts that fzy; cort double mutants wouldarrest in metaphase, with cyclin B localized at the mid-zone. fzy; cort double mutants do indeed accumulate cyclin B largely at thespindle mid-zone and not along the length of the spindle, and are thereforeidentical to cort single mutants. Therefore, the different site ofaccumulation of cyclin B in cort and fzy may reflectdifferent temporal requirements for the APCCort andAPCFzy in meiosis (Swan, 2007).Analysis by western blot showed that Cks30A has little effect onoverall cyclin B levels. However, the immunostaining of eggs from Cks30A revealed that cyclin B was enriched on meiotic spindles. Therefore, Cks30A isalso required for the destruction of cyclin B on spindles in female meiosis,consistent with a role in the activation of the APCCort andAPCFzy complexes (Swan, 2007).In the syncytial embryonic cell cycles, cyclin B associates with themitotic spindle at metaphase, and its destruction on spindles may play a role in anaphase progression. Given that the APCCort and APCFzy are bothrequired for the destruction of cyclin B on the meiotic spindle, it seemslikely that either or both APC complexes would also be involved in localcyclin B destruction on mitotic spindles. cort mutants arrested priorto the assembly of a mitotic spindle and, therefore, the role of Cort inlocalized cyclin B destruction in mitosis could not be determined.Fzy and Cks30A, however, enter into, and arrest in, thefirst mitosis. In both of these mutants, the mitotic arrest is associated with a failure to locally destroy cyclin B, arguing that Cks30A and Fzy are necessary for the local destruction of cyclin B in syncytial mitosis, as well as in meiosis (Swan, 2007).Developmental role and regulation of tag_hash_252______, a meiosis-specific anaphase-promoting complex/cyclosome activatorDuring oogenesis in metazoans, the meiotic divisions must be coordinated with development of the oocyte to ensure successful fertilization and subsequent embryogenesis. The ways in which the mitotic machinery is specialized for meiosis are not fully understood. cortex, which encodes a putative female meiosis-specific anaphase-promoting complex/cyclosome (APC/C) activator, is required for proper meiosis in Drosophila. Cort physically associates with core subunits of the APC/C in ovaries. APC/C(Cort) targets Cyclin A for degradation prior to the metaphase I arrest, while Cyclins B and B3 are not targeted until after egg activation. The regulation of Cort was investigated and it was found that Cort protein is specifically expressed during the meiotic divisions in the oocyte. Polyadenylation of cort mRNA is correlated with appearance of Cort protein at oocyte maturation, while deadenylation of cort mRNA occurs in the early embryo. Cort protein is targeted for degradation by the APC/C following egg activation, and this degradation is dependent on an intact D-box in the C terminus of CORT. These studies reveal the mechanism for developmental regulation of an APC/C activator and suggest it is one strategy for control of the female meiotic cell cycle in a multicellular organism (Pesin, 2007; full text of article).This study demonstrates a physical interaction between Cort and the APC/C strengthens and confirms previous suggestions that cort encodes a functional meiosis-specific APC/C activator. A strong metaphase II arrest phenotype in cort mutant eggs and distant homology to the Cdc20/FZY protein family initially suggested that Cort might function as an APC/C activator. cort has been shown to negatively regulate levels of mitotic cyclin proteins, which is consistent with a role for Cort in activating the APC/C. However, biochemical evidence linking Cort to the APC/C in vivo is crucial for this argument. This study has shown that Cort physically associates with core subunits of the APC/C in ovaries, strongly supporting Cort's role as an APC/C activator (Pesin, 2007).Coordination of the meiotic divisions with oogenesis and the transition from meiosis to restart of the mitotic cell cycle in embryogenesis present unique regulatory challenges for the organism. This study of cortex in Drosophila suggests that developmental control of levels of a meiosis-specific APC/C activator is one way in which meiosis is developmentally regulated. This strategy exploits ongoing regulatory mechanisms occurring during meiosis and embryogenesis: cytoplasmic polyadenylation during oocyte maturation, deadenylation after egg activation, and APC/C-dependent degradation in the early embryo (Pesin, 2007).Cytoplasmic polyadenylation upon oocyte maturation has been shown to translationally activate maternal transcripts of genes that are required for meiotic entry, transition between meiosis I and meiosis II, and metaphase II arrest in vertebrates. cort mRNA is polyadenylated at oocyte maturation; polyadenlyation adds cort to the group of transcripts that are translationally unmasked for entry into the meiotic divisions. What is the signal for polyadenylation of cort? Masked transcripts contain a cis-acting cytoplasmic polyadenylation element (CPE) to which CPE binding protein (CPEB) is bound. Phosphorylation of CPEB upon oocyte maturation triggers elongation of the poly(A) tail and activation of translation. A CPE has not been identified in the 3' UTR of cort, although CPE sequences are quite variable. In addition, no dependence of cort polyadenylation on orb, the CPEB homolog in Drosophila has been identified. Because the orb alleles that were used are hypomorphic, the possibility that polyadenylation of cort is orb/CPEB-dependent cannot be ruled out (Pesin, 2007).Egg activation triggers maternal transcript destabilization in several organisms, some of which occurs through ccr4-dependent deadenylation, and this is likely to be important for localization of maternal transcripts in the embryo and proper zygotic development. This study shows that cort mRNA is deadenylated in the early embryo in a ccr4-dependent manner, but this deadenylation is not required for lowering Cort protein levels. However, a difference in protein levels may not be detected because of the rapid APC/C-dependent degradation of Cort protein that occurs after release of the metaphase I arrest. Deadenylation could serve as a backup mechanism to ensure that Cort protein levels remain low in the early embryo by destabilizing cort mRNA (Pesin, 2007).The APC/C drives degradation of Cyclin B and other substrates during the rapid syncytial mitotic divisions of early embryogenesis in Drosophila. This study found that Cort is targeted for APC/C-dependent degradation by the completion of meiosis in the early embryo. The targeting of an APC/C activator for degradation by another form of APC/C is not unprecedented; APC/CCdh1 targets Cdc20 for degradation in G1 (Pesin, 2007).These data support the conclusion that Cort is targeted by APC/CFZY: (1) FZY is thought to be the only activator present in early embryos; (2) this study shows that cort and fzy interact genetically in a way that is consistent with cort being a negative downstream target of fzy in embryos; (3) in embryo injection experiments, exogenous MYC-Cort is degraded in a D-box-dependent manner in injected embryos. Because the only APC/C activator in early embryos is FZY, degradation of MYC-Cort is likely to occur through APC/CFZY in this assay (Pesin, 2007).It is also possible the APC/CCort regulates itself in a negative feedback loop by targeting Cort for degradation when levels of Cort reach a certain threshold at the end of meiosis. To address this possibility, the degradation of Cort was examined in a homozygous cortQW55 background in which there is no functional Cort protein. CortQW55 mutant protein is not degraded at the transition from mature stage 14 oocytes to unfertilized eggs, unlike in a heterozygous control background. These results suggest that Cort could be targeted by itself, but it remains a possibility that the lesion in the cortQW55 allele prevents an interaction between CortQW55 mutant protein and the APC/C machinery. The lesion does not disrupt the D-box, but it could affect proper folding and structure of the protein. In summary, it is concluded that Cort is targeted for degradation by the APC/C. It is most likely that FZY is the participating APC/C activator, but Cort may also contribute to targeting itself for degradation (Pesin, 2007).Recent work has shown that both cort and fzy are required for the meiotic divisions in Drosophila female meiosis. Mutant analysis suggests that cort and fzy act redundantly to control the metaphase I to anaphase I transition, whereas they seem to act with different temporal and spatial specificity in targeting Cyclin B for destruction along the meiosis II spindles. cort cannot functionally substitute for fzy in the early embryo, suggesting that they target nonredundant sets of substrates. However, the possibility that MYC-Cort was not present in sufficient levels in early embryos for rescue because of low expression levels or protein instability cannot be ruled out. Although MYC-Cort is expressed at high levels in stage 14 oocytes, it appears to be subject to degradation after the completion of meiosis, like the endogenous Cort protein (Pesin, 2007).Furthermore, homozygous cort mutants alone exhibit a strong metaphase II arrest, indicating that the wild-type levels of fzy in this background are not able to act in place of cort to control passage through metaphase II. Finally, FZY is expressed at a uniform level during oogenesis and embryogenesis, which is in contrast to the results in this study showing that Cort expression is specifically upregulated during the meiotic divisions. On the basis of all of these observations, it is thought likely that in addition to the mitotic cyclins, APC/CCort targets a unique set of substrates in meiosis that are not recognized by APC/CFZY. The identification of these meiotic substrates will be crucial for understanding how the meiotic divisions are controlled in the oocyte (Pesin, 2007).The study of meiotic control of the APC/C is especially intriguing in Drosophila, because in addition to cort, a female meiosis-specific activator, the genome contains fizzy-related 2 (fzr2), another member of the Cdc20/FZY family. fzr2 is expressed exclusively in testes and may act as a male meiosis-specific activator. Further study of both cort and fzr2 will be important for understanding differential developmental regulation of the APC/C during meiosis in females versus males (Pesin, 2007).In mitosis, cyclins are targeted sequentially for destruction by the APC/C. Degradation of Cyclin A begins just after nuclear envelope breakdown in prometaphase, while degradation of Cyclin B does not occur until the metaphase to anaphase. Sequential degradation of Cyclin A, Cyclin B, and, finally, Cyclin B3 in Drosophila triggers a series of distinct events leading to exit from mitosis. A similar situation exists in Drosophila female meiosis, in which degradation of Cyclin A by APC/CCort initiates upon nuclear envelope breakdown, but degradation of Cyclin B and Cyclin B3 does not occur until after the metaphase I to anaphase I transition (Pesin, 2007).The difference in timing of Cyclin A and Cyclin B degradation in mitosis is due to regulation of the APC/C by the spindle assembly checkpoint. The spindle assembly checkpoint inhibits APC/CCdc20 from initiating anaphase until all chromosomes are bioriented on the spindle, in part through direct binding of Cdc20 to Mad2 and BubR1. Spindle assembly checkpoint proteins specifically inhibit APC/C-dependent ubiquitination of Cyclin B but not of Cyclin A. APC/CCort may be regulated in a similar manner during meiosis I. Indeed, the spindle assembly checkpoint is likely to function during meiosis I in Drosophila; the conserved spindle checkpoint kinase Mps1 is required for delaying entry into anaphase I to allow for proper segregation of achiasmate homologs and maintenance of chiasmate homolog connections in Drosophila oocytes. Furthermore, a functional Mad2-dependent checkpoint exists during meiosis I in mouse oocytes, and spindle checkpoint components have been shown to regulate the APC/C during meiosis I in C. elegans (Pesin, 2007).To determine whether APC/CCort is regulated by the spindle checkpoint, it was asked if BubR1 or Mad2 physically associate with Cort in stage 14-enriched ovaries. No association with BubR1 or Mad2 was detected. Although this negative result does not rule out the possibility of regulation of APC/CCort by the spindle checkpoint, it suggests that APC/CCort may be subject to other types of regulation that inhibit it from targeting Cyclin B and Cyclin B3 for degradation until after the metaphase I arrest (Pesin, 2007).In conclusion, through the investigation of cortex, a meiosis-specific APC/C activator, one way was found in which the meiotic cell cycle may be developmentally controlled during oogenesis. cort is developmentally regulated by existing post-transcriptional and post-translational mechanisms, resulting in expression of Cort protein being restricted to the meiotic divisions. Further study of APC/CCort will continue to elucidate the ways in which developmental control of the APC/C contributes to proper female meiosis in a metazoan (Pesin, 2007).Evidence that the spindle assembly checkpoint does not regulate APCFzy activity in Drosophila female meiosisThe spindle assembly checkpoint (SAC) plays an important role in mitotic cells to sense improper chromosome attachment to spindle microtubules and to inhibit APCFzy-dependent destruction of cyclin B and Securin; consequent initiation of anaphase until correct attachments are made. In Drosophila, SAC genes have been found to play a role in ensuring proper chromosome segregation in meiosis, possibly reflecting a similar role for the SAC in APCFzy inhibition during meiosis. This study found that loss of function mutations in SAC genes, Mad2, zwilch, and mps1, do not lead to the predicted rise in APCFzy-dependent degradation of cyclin B either globally throughout the egg or locally on the meiotic spindle. Further, the SAC is not responsible for the inability of APCFzy to target cyclin B and promote anaphase in metaphase II arrested eggs from cort mutant females. These findings support the argument that SAC proteins play checkpoint independent roles in Drosophila female meiosis and that other mechanisms must function to control APC activity (Batiha, 2012). REFERENCES Reference names in red indicate recommended papers.Search PubMed for articles about Drosophila Fizzy Acquaviva, C. and Pines, J. (2006). The anaphase-promoting complex/cyclosome: APC/C. J. Cell Sci. 119(Pt 12): 2401-4. Medline abstract: 16763193 Batiha, O. and Swan, A. (2012). Evidence that the spindle assembly checkpoint does not regulate APCFzy activity in Drosophila female meiosis. Genome 55(1): 63-7. PubMed Citation: 22196012Braunstein, I., Miniowitz, S., Moshe, Y. and Hershko, A. (2007). Inhibitory factors associated with anaphase-promoting complex/cylosome in mitotic checkpoint. Proc. Natl. Acad. Sci. 104(12): 4870-5. 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Mol Cell. 5(3): 501-11. 10882135 fizzy: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation| Referencesdate revised: 12 January 2018Home page: The Interactive Fly 2006 Thomas Brody, Ph.D.