EN56CH02-Wolfner ARI 14 October 2010 9:49

Insect Seminal Fluid : Identification and Function

Frank W. Avila, Laura K. Sirot, Brooke A. LaFlamme, C. Dustin Rubinstein, and Mariana F. Wolfner

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853; email: [email protected], [email protected], [email protected], [email protected], [email protected]

Annu. Rev. Entomol. 2011. 56:21–40 Key Words First published online as a Review in Advance on egg production, mating receptivity, storage, mating plug, sperm September 24, 2010

by University of California - San Diego on 08/13/13. For personal use only. competition, feeding, reproduction, Acp

Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org The Annual Review of Entomology is online at ento.annualreviews.org Abstract This article’s doi: Seminal fluid proteins (SFPs) produced in reproductive tract tissues 10.1146/annurev-ento-120709-144823 of male and transferred to females during mating induce nu- Copyright c 2011 by Annual Reviews. merous physiological and behavioral postmating changes in females. All rights reserved These changes include decreasing receptivity to remating; affecting 0066-4170/11/0107-0021$20.00 sperm storage parameters; increasing egg production; and modulating , feeding behaviors, and mating plug formation. In addition, SFPs also have antimicrobial functions and induce expression of antimicrobial peptides in at least some insects. Here, we review re- cent identification of SFPs and discuss the multiple roles these proteins play in the postmating processes of female insects.

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INTRODUCTION SFPs provide intriguing targets for the control of disease vectors and agricultural pests. As we In many insect species, mating initiates a be- discuss below, SFPs alter reproductive and/or Seminal fluid havioral and physiological switch in females, feeding behaviors in a number of , (SFP): protein triggering responses in several processes related including insects that cause economic damage expressed from tissues to fertility. Receipt of seminal fluid—a mix- of the male or spread disease. In many of these species, ture of proteins and other molecules—by the reproductive tract and there are no approved and effective methods to female is a major component of this switch. likely transferred to control the damage they cause. For example, females during mating Insect seminal fluid proteins (SFPs) are the vaccines for tick-borne pathogens have been products of male reproductive tract (RT) se- RT: reproductive developed for a limited number of tick anti- tract cretory tissues—accessory glands (AGs), semi- gens (35) and the principal vectors of malaria nal vesicles, ejaculatory duct, ejaculatory bulb, AG: accessory gland and dengue fever—the mosquitoes and testes. SFPs are transferred to females with Aedes ae- and , respectively—have sperm during mating. They are major effectors gypti Anopheles gambiae been notoriously difficult to control. Thus, the of a wide range of female postmating responses, best current method of limiting these diseases including changing female likelihood of remat- is to control the spread of their insect vectors. ing, increasing ovulation and egg-laying rates, In another area, increased resistance to pesti- changing female flight and feeding behavior, cides has made population control by conven- inducing antimicrobial activities, and modulat- tional means difficult for pests such as the cotton ing sperm storage parameters. Absence of SFPs bollworm/corn earworm from the ejaculate adversely affects the repro- , Helicoverpa armigera (61); the bed bug, (80, 143); ductive success of both sexes. SFPs identified Cimex lectularius and ticks (57). As more is learned about the to date represent numerous protein classes, in- reproductive biology of specific arthropods, cluding proteases/protease inhibitors, lectins, their SFPs may provide tools or targets for prohormones, peptides, and protective pro- the control of disease vectors and agricultural teins such as antioxidants; these protein classes pests. are present in the ejaculate of organisms from The study of SFPs also provides insight into arthropods to (121). While nonpro- the evolutionary patterns of reproductive traits. tein molecules are also present in seminal fluid Although the functional classes of SFPs are con- (e.g., prostaglandins in crickets: 86; steroid hor- served, a significant fraction of individual SFPs mones in mosquitoes: 124), research on the ef- show signs of unusual, often rapid, evolution at fects of seminal fluid receipt has focused largely the primary sequence level. The forces driving on the action of SFPs. Although the focus of this this pattern are not understood, and the study review is on insect SFPs, progress on the iden- of SFPs may allow for their identification and tification and function of SFPs in tick species is

by University of California - San Diego on 08/13/13. For personal use only. dissection. Comparative studies of SFPs, indi- also included. Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org vidually and in aggregate, are important be- The past few years have witnessed an explo- cause ( ) lineage-specific SFPs may be involved sion in the identification and functional analyses a in the reproductive isolation between species; of SFPs in insects due to new proteomic and ( ) highly conserved SFPs or SFP classes may RNA interference technologies. Because ear- b be essential for reproduction; and ( ) SFP di- lier results in this field were reviewed by Gillott c vergence between closely related species may (56), Chen (29), and Leopold (84), we focus illuminate selective pressures underlying SFP here primarily on recent developments, refer- evolution. Recent reviews have focused on the ring readers to those comprehensive reviews for evolutionary dynamics of SFPs (49, 53, 120, details on earlier studies. 148); therefore, we refer the reader to those re- Dissection of the nature and function of in- views and focus here on the nature and function sect SFPs has relevance beyond understanding of SFPs. insect reproductive molecules and their actions.

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IDENTIFICATION OF SEMINAL females during mating (Table 1). For the pur- FLUID PROTEINS poses of this review, proteins within the seminal fluid and transferred to females are called SFPs. The identification of proteins produced in se- Accessory gland Proteins synthesized in male AGs are called cretory tissues of the male RT and demon- protein (Acp): Acps. strated to be, or likely to be, transferred to protein made by, and Most of the Acp/SFP identification stud- expected to be secreted females during mating is the primary step in ies in Table 1 examined RNA or proteins from, the accessory SFP identification. Transcriptomic [expressed found in tissues of the male RT, but did gland of male insect sequence tag (EST), microarray; 5, 16, 20, 30, reproductive tracts not demonstrate SFP transfer during mating. 34, 41, 112, 130, 151, 158, 161, 165] and pro- A novel proteomic method directly identified teomic (6, 10, 32, 48, 50, 75, 136, 140, 149, 153, 146 SFPs (39 previ- 160, 162) methods have given a global view of ously unannotated), 126 SFPs, and proteins produced in male RT glands D. simulans 116 SFPs that are transferred to and, in some cases, of proteins transferred to D. yakuba

Table 1 Recently identified SFPs and RT-expressed in insects No. identified (Ref.) Order Family sp. Method (Ref.) In RT Transferred Diptera Drosophilidae Drosophila simulans EST screen (151), proteomic (48) 57a (151) 3 (48) Drosophila Cumulative review (130), EST 112a (130), 138 (50), 8 (48), melanogaster screen (151), peptide purification 46 (30, 130), 14 (130), (91, 137), proteomic (48, 104, 153, 440 (153), 3 (91, 137, 160), microarray (30, 130) 13a (160), 34a 169) (104, 151) Drosophila yakuba EST screen (16), proteomic (48, 50) 119 (16) 107 (50), 8 (48) Drosophila erecta EST screen (16) 114 (16) — Drosophila EST screen (158), proteomic (75) 54 (158), — mojavensis 786 (75) Tephritidae Ceratitis capitata EST screen (34) 13 (34) — Culicidae Aedes aegypti Bioinf. candidates/RT-PCR (149), 63a (149) 56 (147) proteomic (147) Anopheles gambiae Bioinf. candidates/RT-PCR (41), 46 (41), 25 (140) 15 (140) proteomic (140) erato EST screen/bioinf. filter/RT-PCR 371 (161) 25 (162)

by University of California - San Diego on 08/13/13. For personal use only. (161), proteomic (162) Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org Heliconius EST screen/bioinf. filter/RT-PCR 340 (161) 10 (162) melpomene (161), proteomic (162) Hymenoptera Apidae Apis mellifera Proteomic (10, 32) 69 (32) 33 (32), 57 (10) Coleoptera Tenebrionidae Tribolium castaneum Microarray (112) 112 (112) — Orthoptera Gryllidae Allonebrius EST screen (20) 183 (20) — Gryllus firmus EST screen (5, 20) 247 (5, 20) — Gryllus EST screen (5), proteomic (6) 277 (5) 22 (6) pennsylvanicus Arachnida: Ixodidae Amblyomma EST screen (165) 35 (165) — Ixodida hebraeum

aCandidate SFPs were based on criteria of accessory gland–specific or –enriched expression and/or presence of a predicted secretion signal sequence. Abbreviations: Acp, accessory gland protein; EST, expressed sequence tag; RT, reproductive tract; RT-PCR, reverse transcriptase–polymerase chain reaction; SFP, seminal fluid protein.

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females during mating (48, 50). Findlay et al. diction of SFPs by sequence comparison much (50) fed females a diet enriched in 15Nsothat easier. For example, comparative structural the females produced isotopically heavy pro- modeling suggested the structure/function of teins. After these females were mated to un- 28 predicted Acps of D. melanogaster males labeled males, only proteins transferred from (105). FlyBase annotations to D. melanogaster males were detected when the female RTs were genes were used to predict the functional analyzed by mass spectrometry. This method classes of 240 candidate SFPs in D. mojaven- was subsequently adapted to identify trans- sis (75). Cross-species comparisons to D. sim- ferred SFPs in Aedes aegypti (147). ulans and D. yakuba led to the identification SFPs identified in these studies (Table 1) of 19 D. melanogaster proteins previously unre- include peptides and prohormones and pro- ported as SFPs (50). The newly identified puta- tein classes predicted to play roles in numer- tive SFPs of these species fall into the same cat- ous functions including sperm binding (lectins egories previously identified in D. melanogaster and cysteine-rich secretory proteins), proteol- (105). ysis, lipases, and immunity-related functions. Aside from putative function based on se- These protein classes are seen in the ejaculates quence analysis, direct assessment of specific of several insect species, providing evidence SFP tissue targets within the mated female may that, although the primary sequence of some hint at those SFP functions (e.g., localization SFPs evolves rapidly, the protein classes repre- to the sperm storage organs may suggest a sented in seminal fluid are constrained (104). role in sperm storage or maintenance, as seen Further, examining the seminal fluid of the for a network of D. melanogaster Acps; 132). extensively studied Drosophila species reveals Thirteen D. melanogaster Acps target multiple rapid gain/loss of Acp genes to be a common tissues within the mated female RT, each hav- feature of Drosophila seminal fluid evolution (50, ing a unique targeting pattern (133). In addi- 104), suggesting that Acp genes evolve de novo, tion, a subset of Acps leave the female RT and perhaps from noncoding DNA (15, 159). How- enter the hemolymph (90, 99, 119, 133), poten- ever, even as much of the knowledge of insect tially reaching nervous and/or endocrine sys- SFPs has been obtained via studies in Drosophila tem targets. species, a recent proteomic study showed that More direct methods have also identified Apis mellifera (honey bee) SFPs shared more se- the roles of specific SFPs in processes such quence similarities with human SFPs than with as regulation, behavior, and physiological D. melanogaster SFPs (10). Therefore, future processes such as sperm storage. These results studies of SFPs across representative taxonomic are discussed below. groups should elucidate the fascinating evolu-

by University of California - San Diego on 08/13/13. For personal use only. tionary history of these proteins.

Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org Changes Changes in female gene expression postmating FUNCTION OF IDENTIFIED have been examined in D. melanogaster and, SEMINAL FLUID PROTEINS to a lesser extent, in An. gambiae and Apis Historically, insect SFP function has been an- mellifera.InD. melanogaster, the effect of SFPs alyzed by several approaches, including the in- and sperm on transcriptional change in mated jection of a purified SFP or protein fractions females has been dissected by microarray into virgin females, biochemical analysis, re- analyses. Levels of over 1,700 transcripts are moval of putative SFPs by RNAi or altered at 1–3 h postmating in females (82, 95). in Drosophila, and ectopic expression of SFPs in The mating-dependent genes have predicted unmated Drosophila females. Moreover, the in- functions in a multitude of biological processes, creasing availability of genomic and predicted including , immune defense, and protein annotations has made functional pre- protein modification. However, only a handful

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of the mating-responsive changes in RNA Sex peptide (SP), a 36-amino-acid Acp with levels are greater than twofold, consistent with roles in egg production, receptivity, feeding, the hypothesis that sexually mature females and sleep behaviors in mated females (25, 69, SP: sex peptide are poised to respond to mating (64, 95). By 85), affects expression of 52 genes in the head 6 h postmating, larger-magnitude changes in and abdomen of mated females. The majority RNA levels are observed in a smaller number of these RNAs changed only two- to three- of genes (94). After a second mating, the fold (39). In the head, SP regulated RNA levels expression of immunity-related genes is more of genes for proteins involved in metabolism, pronounced (67), suggesting that previously proteolysis, signal transduction, and transcrip- mated females have sufficiently upregulated tion. In abdomens, the SP upregulated antimi- metabolic and/or structural genes required for crobial peptide genes via the Toll and IMD postmating processes (e.g., ovulation and egg pathways (115); a C-terminal motif of SP is re- laying) to continue. sponsible for mediating this effect (39). Despite In the lower RT (the lower common the induction of antimicrobial peptide genes by oviduct, seminal receptacle, female AGs, mating, hemolymph challenge did not detect an spermathecae, and anterior uterus), the levels immune response in mated females (47, 167). of over 500 transcripts are changed postmating RNA levels for 141 genes in An. gambiae (92). A distinct shift—from gene silence to females experience changes at 2, 6, and 24 h activation—is observed soon after the onset postmating (141). The number of genes with of mating (92). A dramatic peak in differential changes in expression levels twofold or greater gene expression is seen 6 h postmating (92), increased with time since mating. Changes in consistent with the whole-body transcriptome transcript levels of many of these genes per- results described above (94). In the oviduct, sist for at least 4 days postmating. Mating- mating induces an upregulation of immune- responsive expression changes were examined related transcripts and increases levels of RNA specifically in the head, the gut, the ovaries, the for cytoskeleton-related proteins (72). Some lower RT (tissues below the ovaries), and the oviduct mating-responsive genes respond only two major organs of the lower RT (the atrium, to the first mating, and others to both the first where the ejaculate is received, and the sper- and second matings (73). The female RT tran- matheca). In both the gut and the lower RT, the scriptome suggests that the structural changes expression levels of several genes change post- occurring after the first mating (presumably mating. Many of these are predicted proteoly- due to mating-responsive gene expression) are sis regulators. In the spermatheca, a predicted sufficient for continued postmating processes. vitellogenin was also highly upregulated post- Because some of the mating-dependent gene mating. As with D. melanogaster, Rogers et al.

by University of California - San Diego on 08/13/13. For personal use only. expression change is due to SFP receipt (95), (141) conclude that the female atrium is poised Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org transcriptome change in mates of males lacking to respond to mating. However, they propose specific SFPs was investigated. The ovulation- that the spermatheca may rely on signals re- inducing SFP ovulin and the sperm storage pro- ceived during mating to regulate genes involved tein Acp36DE do not contribute extensively to in sperm storage and maintenance. female transcriptome change at 1–3 h postmat- Large-scale transcriptional changes occur ing (94). However, two other SFPs, Acp29AB in the ovaries and brains of Apis mellifera and Acp62F, substantially affect the female queens postmating (78, 79). In the ovaries, transcriptome (94). Surprisingly, Acp29AB and 366 transcripts are differentially expressed post- Acp62F contribute to the upregulation of genes mating, with the regulated genes largely in- involved in egg production and muscle de- volved in cell division, gametogenesis, repro- velopment, even though analyses of mates of duction, and oogenesis (78). The RNA levels Acp29AB- or Acp62F-null males do not detect of 971 genes are differentially expressed in fe- ovulation or egg-laying defects (102, 169). male A. mellifera brains postmating, with an

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overrepresentation of genes involved in protein and increased innervation of this tissue (72). folding, protein catabolism, and the stress re- Postmating increases in neural activity to the sponse (78). The types of genes regulated by oviduct occur in the form of vesicle release from mating in A. mellifera overlap with those seen RT nerve termini and are modulated distinctly in the previously mentioned D. melanogaster by mating, Acp receipt, and sperm receipt. studies (e.g., genes involved in the immune re- Mating and/or the receipt of Acps or sperm sponse), suggesting that the postmating tran- has differing effects on vesicle release in differ- scriptional response may be conserved across ent regions of the RT at different times post- species (79). In addition, insemination quan- mating, inferred from the intensity of labeled tity affects gene expression in the brain (138), vesicles (64). Immediate postmating change in suggesting that ejaculate volume and, possibly, neural vesicle release occurs in the lower com- quantity of specific SFPs received may act as mon oviduct, seminal receptacle, and uterus. At cues for this processes in mated A. mellifera 3 h postmating—when females are ovulating at females. high rates and egg production has reached max- imal levels (18)—vesicle release is inhibited in the common oviduct and lateral oviducts, with Antimicrobial Functions of SFPs Acps modulating changes in nerve termini in- Aside from roles in mediating the upregulation nervating the seminal receptacle (64). of antimicrobial genes in mated females (95, SFP receipt also affects the lower RT, in- 115), some SFPs have an intrinsic antimicro- ducing a series of conformational changes in bial function. Three D. melanogaster SFPs (from the uteri of mated D. melanogaster females, ini- the AG and ejaculatory duct) have antimicro- tiating during the first moments of copulation bial activity on Escherichia coli growth in vitro and continuing after mating has ended (1). At (88). An additional three D. melanogaster SFPs least part of this process aids in the storage of have antimicrobial activity in vivo—upon ec- sperm, allowing them to access the storage or- topic expression, they reduce bacterial loads in gans. Acps, and not sperm, are the ejaculatory females infected with Serratia marcescens (103); components required to trigger these changes the relationship of these three genes to the three (1). The Acp(s) that initiates this process is un- identified biochemically is unknown. Although known. However, Acp36DE is essential for the analogous antimicrobial activities have not been progression of these changes (8). Incomplete detected in the seminal fluid of the bed bug, progression of these changes in the absence C. lectularius, its seminal fluid does contain bac- of Acp36DE leaves sperm lagging in the mid- teriolytic activity, specifically, a lysozyme-like uterus instead of forming a dense mass adjacent immune activity capable of degrading bacteria to the sperm storage organ entrances (8). This

by University of California - San Diego on 08/13/13. For personal use only. (111). These findings suggest that SFPs might finding, coupled with the abnormally low num- Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org play a protective role within the RTs of mated bers of sperm stored in Acp36DE-null mates females, possibly aiding females’ ability to clear (19, 108), suggests that the postmating uterine microbes introduced during mating. conformation changes aid sperm movement, en masse, toward storage. An. gambiae female RTs undergo structural Structural and Conformational changes upon mating (141). In virgin females, Changes of the Female RT the apical cytoplasm of atrium cells has ex- The receipt of seminal fluid induces physiologi- tensive, smooth endoplasmic reticulum sur- cal and structural changes of female RTs. In the rounded by high numbers of mitochondria. oviduct of D. melanogaster females, tissue-wide The basal poles of the cells have a high den- postmating changes include the differentiation sity of rough endoplasmic reticulum. In mated of cellular junctions, remodeling of the extra- females, both the smooth and the rough en- cellular matrix, increased myofibril formation, doplasmic reticula mostly disappear, and the

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mitochondria become distributed throughout targets SP to the storage organs in mated the cells. Rogers et al. (141) propose that these females (132). SP, responsible for eliciting nu- structural changes may result in a barrier to merous postmating responses, is unique in ex- remating. erting its effects on mated females for several days. The long-term effects of SP result from its physically binding sperm, maintaining its pres- Sperm Maintenance in, and Release ence in the female RT as long as sperm remain from, Storage in storage (114). Sperm binding is a function In addition to roles of SFPs in sperm storage, of the N terminus of the peptide; the C ter- SFPs are involved in the maintenance of sperm minus of SP—which contains the receptivity- viability in, and their release from, storage (e.g., modulating activity—is gradually cleaved from 170). Seminal fluid secretions from male AGs sperm tails (114). These findings suggest that of both the honey bee, A. mellifera, and the leaf- the phenotypes (in sperm storage but also in re- cutter ant, Atta colombica, promote sperm viabil- ceptivity and egg laying) elicited by the absence ity (37, 38). However, AG secretions from one of CG9997, CG1652, CG1656, and CG17575 male do not positively affect the viability of an- from the ejaculate may be attributable to the other male’s sperm (36). In ants and bees, the inability of SP to localize to sperm. effects of AG secretions on sperm survival differ SFPs do not affect sperm release. Acp29AB, between monandrous and polyandrous species a predicted lectin, is needed for sperm to be re- (36). AG secretions from monandrous species tained within the sperm storage organs. Sperm promote sperm survival, even when the semi- from males homozygous for a Acp29AB loss-of- nal fluid and sperm are from different males. function mutation enter into but are not well AG secretions from polyandrous species, how- maintained within storage, consequently far- ever, are detrimental to sperm survival—even to ing poorly in a sperm-competitive environment sperm of related males—suggesting a sensitive (169). The latter result is likely due to the re- recognition system exists during sperm compe- duced numbers of stored sperm—a phenotype tition (36). The negative effects of AG fluid on analogous to that seen in mates of Acp36DE- sperm survival are mitigated by spermathecal null males (28). secretions in the leafcutter ant, suggesting that females of this species control ejaculate com- petition once sperm are stored (36). Similarly, Receptivity to Remating D. melanogaster seminal fluid has a protective Decreased sexual receptivity of mated females function, improving the survival of even rival occurs in a wide range of insects, and it has sperm (66). been suggested that inducing this change in

by University of California - San Diego on 08/13/13. For personal use only. In D. melanogaster, Acps are necessary for females is of benefit to males by decreas- Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org the efficient utilization of stored sperm, as the ing the likelihood of sperm competition. In few sperm stored in the absence of Acps are not D. melanogaster, the receipt of SFPs changes fe- used to fertilize eggs (170). Utilization of sperm male behavior—mated females actively reject involves their retention in, and release from, courting males. The SP plays a central role in storage (131). The removal of five Acps, indi- inducing this change in female receptivity (26, vidually, from the male ejaculate led to sperm 60, 85, 132, 173, 174). The four Acps required retention in both storage organs after mat- for SP sperm localization also influence recep- ing (7, 131). Four of these proteins (CG9997, tivity (131). How SP accomplishes its regula- CG1652, CG1656, CG17575—a serine pro- tion of female receptivity is not known, but its tease, two C-type lectins, and a cysteine-rich action requires a G-coupled-protein receptor secretory protein, respectively) are required for (174) and specific neurons (60, 173) in females. the localization of the fifth protein, SP, to C. capitata females are less receptive to male sperm (132), acting in a functional pathway that courtship and are less likely to mate for several

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days after a single mating than are virgin females into unmated H. armigera females. This ef- (70, 97). Sperm storage may play a role in female fect occurs in a dose-dependent fashion (44, receptivity in this species, as females who store 45). In addition, antibodies raised against the less sperm postmating are more likely to remate D. melanogaster SP detect signals from H. sooner (97, 100). In addition, C. capitata females armigera male RTs (107). switch from a male odor preference There is growing evidence that SFPs have to a host plant odor preference postmating (70), important effects on female postmating behav- a switch possibly mediated by factors in male ior in lady beetles (117, 118), seed beetles (101, seminal fluid. 144, 172), and ground beetles (152). Injection When mated to irradiated sterile males (and of testis extracts reduces the probability of mat- thus subsequently storing little or no sperm), ing at 3 h and 2 days postinjection, whereas in- Queensland fruit fly females, Bactrocera tryoni, jections of AG extracts reduce the probability show no difference in sexual receptivity when of mating only at 2 days postinjection. Further, compared with mates of nonirradiated males injection of a small-molecular-weight (<3kDa) (58), suggesting that products of the seminal fraction of male RTs results in a short-term de- fluid, not sperm, are responsible for the reduced crease in the probability of mating (1 and 3 h postmating receptivity observed. In support of postinjection), whereas injection of a higher- this hypothesis, virgin B. tryoni females injected molecular-weight (>14 kDa) fraction results with male RT extracts experienced diminished in longer-term inhibition of mating (2 and sexual receptivity and shorter copulation times 4 days after injection; 171). In the ground beetle when subsequently mated, similar to behaviors Leptocarabus procerulus, injections of either seen in previously mated females (126). That testes or AG homogenates into virgin fe- B. tryoni male AG size decreases after mating males independently decrease the probability of suggests that this tissue is a major site of SFP mating (152). synthesis (127). In An. gambiae, male reproductive gland proteins also mediate female likelihood of re- Egg Production mating (23, 24). This conclusion was initially A frequent effect of seminal fluid receipt is an suggested by studies involving females mated increase in egg production, ovulation, and/or to hybrid males with reduced AGs (23, 24) and egg-laying rates in female insects. Transferring subsequently verified by injections of male AG SFPs that upregulate these processes can bene- homogenates into virgin females (145). fit males, ensuring their sperm fertilize the max- In several moth species, sexually receptive imum number of eggs before the female re- females produce sex to attract mates, and can also benefit females, allowing

by University of California - San Diego on 08/13/13. For personal use only. mates. Sex pheromone production declines increased egg production only when sperm are Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org substantially after mating. Calling behaviors present to fertilize those eggs. D. melanogaster cease and oviposition behaviors initiate (13). SP stimulates egg laying in mated females (56, In several of these species, pheromone pro- 130), and the long-term persistence of this ac- duction is under neuroendocrine control, re- tivity requires the four Acps that localize SP to sulting from the release of pheromone biosyn- sperm (114, 131, 132). thesis activating neuropeptide (PBAN) into the The prohormone-like SFP ovulin female hemolymph (128). Reduction of fe- (Acp26Aa) stimulates ovulation (62). Its male pheromone levels postmating is a con- mechanism is unknown but could involve two sequence of PBAN reduction in the female nonmutually exclusive mechanisms: directly hemolymph (106). Synthetic D. melanogaster via ovulin interaction with neuromuscular SP and the pheromone suppression peptide targets along the lateral oviducts of the female HezPSP—from Helicoverpa zea AGs (76, 129)— RT, or indirectly by affecting the activity of suppress pheromone production after injection the neuroendocrine system (62, 64). Ovulin

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is proteolytically cleaved in the female RT in Mating Plug Formation a step-wise manner (reviewed in Reference In several insect species, a mating plug is formed 148), a process dependent on at least one within the female RT during and/or after mat- other Acp, CG11864 (134), a predicted astacin ing. Mating plugs often contain SFPs, and their family metalloprotease that is itself cleaved in formation is dependent on receipt of SFPs. the male RT during transfer to females (134). Mating plugs have a wide range of functions, Ectopic expression of full-length ovulin, or such as in sperm competition (17, 42, 146); for- either of ovulin’s two C-terminal cleavage mation of a physical barrier to remating, as in products, is sufficient to stimulate ovulation in butterflies (110); and switching off female re- unmated females (63), suggesting that ovulin ceptivity entirely, as in the bumble bee, Bombus cleavage may increase its activity by generating terrestris (11). more bioactive components of the protein. In D. melanogaster, a mating plug is formed Little is known about SFP-mediated effects shortly after mating begins. This structure has on ovulation in other insect species. In Apis two major regions: a posterior region composed mating stimulates vitellogenesis and mellifera, of ejaculatory bulb proteins (PEB-me, PEBII, oocyte maturation in females (79, 154). In Ae. and PEBIII; 22, 91) and an anterior region com- , male reproductive gland proteins mod- aegypti posed of Acps (91). Evidence for a role of the ulate an increase in oviposition (reviewed in mating plug, and the SFPs within it, in re- References 31, 56, 77, and 149). In Anopheles ducing female receptivity has been shown in sp., there is indirect evidence that SFPs regu- D. melanogaster: Mates to PEBII knockdown late female fecundity (43, 68): Males have an- males (who form smaller mating plugs) are giotensin converting enzyme (ACE) activity in more receptive to remating than controls in their reproductive glands and females mated to the short term (4 h; 22). These results suggest males fed ACE inhibitors lay fewer eggs than that the mating plug mediates a short-term de- females mated to control males. In , H. armigera cline in receptivity before the long-term effects crude extracts of the male AGs stimulate egg of other SFPs set in. A similar effect is seen maturation and oviposition when injected into in D. hibisci, in which the mating plug inhibits virgin females, similar to effects seen after mat- courtship by subsequent males and reduces fe- ing (71). The receipt of the male ejaculate in- male receptivity (123). In D. hibisci, the mating creases female reproductive rates C. lectularius plug is also suggested to facilitate sperm stor- in terms of lifetime egg production, and fe- age by preventing the back flow of sperm away males receiving more ejaculate enter reproduc- from the storage organs (122). tive senescence later than females who receive In An. gambiae, the mating plug is neces- less ejaculate (135). These findings suggest that sary for proper sperm storage but does not pre-

by University of California - San Diego on 08/13/13. For personal use only. ejaculate components may compensate for the vent remating by the female (140). Further, a Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org costs of elevated reproductive rates by delaying male AG-specific transglutaminase is necessary reproductive senescence in this species. Ejac- to form the mating plug (140). Although trans- ulate volume affects seed beetle fecundity, as glutaminases are made in other mosquito females receiving smaller ejaculates have lower species, male AG-specific transglutaminases are fecundity than females receiving larger ejacu- only found in mosquitoes that form mating lates, although this effect is not seen in all bee- plugs (140). tle species (101, 144). In the twospotted lady In D. mojavensis and related species, females beetle, females ingest SFPs Adalia bipunctata, experience an insemination reaction mass (113). in the male spermatophore. Females prevented Although not a mating plug per se, it fills the from consuming spermatophores have a longer entire uterus and persists for hours, absorb- latency to oviposition as well as a lower dura- ing nutrients from the male ejaculate that are tion of resistance to remating than do control incorporated into female somatic tissue (93). females (117).

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Proteins with sequence similarity to larval clot- overfeeding or to the energetic costs of egg ting factors in D. melanogaster (75) found in the production (14). AGs of D. mojavensis, along with proteins with In female ticks, the feeding cycle consists of fibrinogen domains found in D. mayaguana (3) a preparatory phase, a slow feeding phase, and and D. mojavensis (75) AGs, are good candidates a rapid feeding phase (12). After completion of for proteins involved in forming the clot-like this cycle, females will have increased in weight insemination reaction mass. almost 100-fold—an engorgement process that lasts ∼6–10 days and completes before females lay an egg batch (12). The transition weight Longevity between the slow and rapid feeding phases is termed the critical weight. Most virgin females The longevity of mated females is decreased in do not feed past the critical weight (54, 59). Ini- some (e.g., D. melanogaster: 166) but not all (e.g., tiation of the rapid feeding phase is dependent cricket: 157) insects. In D. melanogaster, Acps on the receipt of a testis/vas deferens–derived mediate at least part of this longevity reduction engorgement factor called voraxin (74, 87, 164). (27) for reasons that are as yet unknown, and Voraxin consists of two components (voraxin α SP plays a major role in Acp-mediated decrease and β) and is sufficient to stimulate engorge- in longevity (166). In addition, SP and three ment of feeding when injected into virgin fe- other Acps (the protease inhibitors Acp62F and males (164). In addition, female feeding to en- CG8137, and the peptide CG10433) are toxic gorgement was reduced by 74% when reared on to D. melanogaster upon ectopic expression (89, rabbits immunized with recombinant voraxin 103), possibly reflecting the negative effect of (164). Paradoxically, RNAi knockdown of vo- their action under normal mating conditions. raxin had no effect on female engorgement after However, the mechanism(s) by which these mating with knockdown males (150), and exper- Acps decrease longevity is unknown, and as ec- iments with the American dog tick, Dermacen- topic expression produces protein levels higher tor variabilis, found that silencing engorgement than normally encountered during mating, the factor α and β homologs via RNAi failed to re- toxicity observed may not reflect the true effects duce engorgement (40). Thus, the feeding role of these Acps, suggesting that the longevity ef- of these proteins has yet to be fully ascertained. fects associated with mating may be an indirect effect of SFP receipt (102). Activity Levels The increase in D. melanogaster female feeding Feeding observed postmating coincides with a decrease

by University of California - San Diego on 08/13/13. For personal use only. SFPs affect the feeding behavior of some fe- in female siesta sleep (a quiescent sleep-like Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org male arthropods. D. melanogaster SP increases state) postmating (69). This effect is mediated female feeding postmating (25). This behav- by receipt of SP, which decreases siesta sleep ioral change is substantially reduced in egg- by 70% (69), consequently increasing foraging less females and increased in virgin females and egg-laying activity of mated females. with experimentally elevated rates of egg pro- In conjunction with the negative impact duction, suggesting that increased feeding is of SP on female life span (166), the effect of tied to the postmating increases in ovula- SP on female longevity may be the result of tion and/or oviposition (14). However, egg-less increases in stress due to sleep deprivation and D. melanogaster females continue to show to increased locomotor activity (69). mating-dependent decreases in life span similar Flight behavior is altered postmating in to that of fertile, wild-type females, suggesting A. mellifera queens. At ∼1–2 weeks of age, that the decreased longevity observed in mated queens mate multiply during mating flights— D. melanogaster females is not attributable to inseminated by an average of 12 males (155).

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Mating makes queens less likely to attempt of traditional neural signaling systems. For flight again (79). In addition, insemination by example, ovulation and subsequent egg laying single versus multiple drones affects several be- are presumably mediated by contraction of the SPR: sex peptide haviors, including flight behavior (79), suggest- female RT. The biogenic amine octopamine receptor ing that queens might use ejaculate volume (and (OA) is an important regulator of ovulation- possibly contents) as a cue for flight attempts. related contractions of the female RT in Locusta (109), Stomoxys (33), and Drosophila (96, 98, 139). Further, RT extracts from male Stomoxys FEMALE EFFECTORS OF induce changes in muscle contraction in female SEMINAL FLUID PROTEINS RTs (33). The Drosophila receptor, OAMB, Little is known about the female molecules that critical for the ovulation effect, is selectively interact with SFPs and are subsequently re- expressed in oviductal epithelium (83). OA sponsible for inducing the myriad postmating mediates ovary muscle contraction and oviduct changes observed in insects and other arthro- muscle relaxation. These opposing effects may pods. A notable exception is the receptor for serve to expel the egg from the ovary while the D. melanogaster SP, the sex peptide re- facilitating entry into the common oviduct (81, ceptor (SPR). SPR, identified in an extensive 96, 156). Perhaps signaling systems, such as OA, RNAi screen, is a G-protein-coupled receptor or their proximate downstream targets may that acts through a cAMP-dependent pathway serve as substrates that are modulated by SFPs. (174). The ejaculatory duct peptide DUP99B, which has a C terminus similar to that of SP, also interacts with SPR (137, 174). SPR ex- SOCIAL BEHAVIOR EFFECTS pression in neurons that express the sex-specific The amount of SFPs transferred may depend, fruitless transcript is necessary and sufficient to in part, on the mating status of males and fe- reestablish the receptivity and egg-laying ef- males and their social environment before or fects of SPR (174). Further, SPR expression is during mating. Mating status of both sexes necessary in sensory neurons innervating the can affect the magnitude of female postmat- female RT that express the pickpocket marker, ing responses (51, 65, 116). In a number of in- possibly reducing the output of these neurons to sects, females mated to recently mated males the central nervous system (60, 173). The abil- show less pronounced postmating changes in ity of the D. melanogaster SP to interact in vitro receptivity and egg production than do females with Ae. aegypti and Bombyx mori SPR orthologs mated to virgin males (e.g., D. melanogaster: (174) suggests that SFPs analogous to the SP 65; Anastrepha obliqua: 116). In some insects, are present in the seminal fluid of these, and mates of nutritionally stressed males have less

by University of California - San Diego on 08/13/13. For personal use only. potentially other, insects. This interpretation is pronounced postmating changes in receptivity Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org consistent with the ability of D. melanogaster SP to remating than mates of control males (4). to induce postmating responses when injected These studies suggest that males are limited in into unmated H. armigera females (45, 46, 107). the amount of SFPs they can produce and/or Ultimately, SFPs must interact in the store at a given time and that SFP production context of the female RT. Thus, progress may be resource limited. in understanding the signaling mechanisms Given this potential limitation and the im- involved in insect reproductive processes may portance of SFPs in determining male repro- illuminate mechanisms of SFP modulation in ductive success (e.g., via effects on sperm stor- female physiology and behavior. Recent reviews age, egg production, and remating), selective have addressed neuropeptide control of insect pressures should exist for males to allocate the hormones and sexual receptivity (55) in the ejaculate in a manner that maximizes their re- reproductive physiology of the locust Locusta productive success. One way this could be ac- migratoria (e.g., 81). SFPs may act upstream complished would be to allocate more SFPs

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to females mated under conditions of higher receptor SPR. Proteins secreted from female sperm competition risk (elevated either be- RTs, including the sperm storage organs, offer cause the female has previously mated or be- an exciting list of candidates to test for roles cause other males are in the vicinity of the in mediating SFP responses (2, 9, 125). That mating pair). There is support for such strate- hundreds of SFPs are transferred to females gic allocation of sperm in a number of insect suggest that many molecular pathways may species, including beetles, crickets, and medflies be involved in female postmating responses. (reviewed in Reference 163). Recent evidence Interactions affect protein localization (e.g., SP has demonstrated strategic allocation of SFPs to sperm; 132) and proteolytic cascades (134) as well (reviewed in Reference 148). Briefly, in D. melanogaster, but much needs to be done D. melanogaster males transfer more sex pep- to characterize these and other pathways. tide when they are exposed to another male Second, what extrinsic factors affect the pro- before and during mating than when they are duction and transfer of SFPs and the magnitude alone with the female before and during mating of their effects on mated females? Few studies (168). Other evidence is consistent with the hy- have investigated this question, but those that pothesis that strategic SFP allocation increases have suggest that effects of SFPs on female post- male reproductive success. For example, the mating response are influenced by a number of mates of males exposed to other males before factors. For example, adult female nutrition al- mating have longer latencies to remating and ters the magnitude of the effects of SP on dif- higher fecundity than do mates of males not ex- ferent phenotypic traits, which show that the posed to other males before mating (21). Thus, responses to mating in general, and SFPs in par- D. melanogaster males are able to adjust their ticular, can vary under different environmental ejaculate composition in response to risk of conditions (52, 142). Furthermore, males trans- sperm competition, an adjustment that appears fer different amounts of SFPs in different con- to increase male reproductive success. Future texts, such as a competitive environment (168). research in this area should test for strategic These effects observed in the laboratory suggest SFP allocation in other insect species. that modulation of SFP action and allocation in natural settings will be important to consider for fundamental reasons and also in insect pest CONCLUSIONS control. SFPs have roles in modulating many female be- Third, how do different proteins come to havioral and physiological processes across a play similar roles in different species, and what wide range of insect species. The recent rapid forces lead to the rapid SFP sequence evolu- pace of technological advances in transcript and tion? Conservation of the effects of SFPs on

by University of California - San Diego on 08/13/13. For personal use only. protein identification has resulted in greatly in- females and of SFP classes across the seminal Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org creased knowledge of suites of SFPs in a num- fluid of a wide taxonomic range indicates fun- ber of insect species, and the roles of individual damentally conserved roles for SFPs. Yet, in- SFPs in female postmating responses are be- dividual SFPs tend to evolve rapidly and are ing elucidated. However, several questions still not well conserved even across closely related need to be addressed. species. Studies of SFP evolutionary dynamics First, how do male SFPs interact with each will provide insight not only into SFP evolu- other and with female molecules to effect the tion but also into the mechanisms by which changes observed in mated females? Down- sexual selection shapes the structure and func- stream female effectors with or through which tion of molecules. These are only a small sam- SFPs exert their functions remain unknown, pling of the fascinating questions that await with the exception of D. melanogaster SP and its answers.

32 Avila et al. EN56CH02-Wolfner ARI 14 October 2010 9:49

SUMMARY POINTS 1. SFPs have roles in modulating female behavioral and physiological processes in numerous insect species. SFPs are being identified in an increasing number of insects. 2. SFPs and proteins of Diptera, Lepidoptera, Hymenoptera, Coleoptera, Orthoptera, Hemiptera, and Ixodida species are described. 3. Mating and SFPs mediate female postmating responses in processes such as transcrip- tional and RT structural changes, upregulation of antimicrobial peptide genes, altered receptivity to remating, sperm storage, mating plug formation, postmating feeding, and female activity levels.

FUTURE ISSUES 1. How do male SFPs interact with each other and with female molecules to effect the changes observed in mated females? 2. How do extrinsic factors (e.g., nutrition and differing social conditions) affect the pro- duction and transfer of SFPs and the magnitude of their effects in mated females? 3. How do SFPs regulate similar reproductive processes across numerous species in the face of selective pressures and rapid evolution? The forces that drive these changes ought to be examined.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We would like to thank our colleagues in the reproductive biology and SFP fields for useful discussion, Jessica Sitnik and Erin Kelleher for helpful comments on the manuscript, and NIH grant RO1-HD038921 (to MFW) for support. We apologize to colleagues whose work could not by University of California - San Diego on 08/13/13. For personal use only.

Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org be included or receive detailed description because of length restrictions. Brooke A. LaFlamme and C. Dustin Rubinstein contributed equally to this review.

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40 Avila et al. EN56-Frontmatter ARI 28 October 2010 7:29

Annual Review of Entomology Contents Volume 56, 2011

Bemisia tabaci: A Statement of Species Status Paul J. De Barro, Shu-Sheng Liu, Laura M. Boykin, and Adam B. Dinsdale ppppppppppppp1 Insect Seminal Fluid Proteins: Identification and Function Frank W. Avila, Laura K. Sirot, Brooke A. LaFlamme, C. Dustin Rubinstein, and Mariana F. Wolfner ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp21 Using Geographic Information Systems and Decision Support Systems for the Prediction, Prevention, and Control of Vector-Borne Diseases Lars Eisen and Rebecca J. Eisen pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp41 Salivary Gland Hypertrophy Viruses: A Novel Group of Insect Pathogenic Viruses Verena-Ulrike Lietze, Adly M.M. Abd-Alla, Marc J.B. Vreysen, Christopher J. Geden, and Drion G. Boucias pppppppppppppppppppppppppppppppppppppppppppppp63 Insect-Resistant Genetically Modified Rice in China: From Research to Commercialization Mao Chen, Anthony Shelton, and Gong-yin Ye ppppppppppppppppppppppppppppppppppppppppppppp81 Energetics of Insect Diapause Daniel A. Hahn and David L. Denlinger ppppppppppppppppppppppppppppppppppppppppppppppppp103 Arthropods of Medicoveterinary Importance in Zoos

by University of California - San Diego on 08/13/13. For personal use only. Peter H. Adler, Holly C. Tuten, and Mark P. Nelder pppppppppppppppppppppppppppppppppppp123 Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org Climate Change and Evolutionary Adaptations at Species’ Range Margins Jane K. Hill, Hannah M. Griffiths, and Chris D. Thomas ppppppppppppppppppppppppppppppp143 Ecological Role of Volatiles Produced by Plants in Response to Damage by Herbivorous Insects J. Daniel Hare ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp161 Native and Exotic Pests of Eucalyptus: A Worldwide Perspective Timothy D. Paine, Martin J. Steinbauer, and Simon A. Lawson pppppppppppppppppppppppp181

vii EN56-Frontmatter ARI 28 October 2010 7:29

Urticating Hairs in Arthropods: Their Nature and Medical Significance Andrea Battisti, G¨oran Holm, Bengt Fagrell, and Stig Larsson pppppppppppppppppppppppppp203 The Alfalfa Leafcutting Bee, Megachile rotundata: The World’s Most Intensively Managed Solitary Bee Theresa L. Pitts-Singer and James H. Cane ppppppppppppppppppppppppppppppppppppppppppppppp221 Vision and Visual Navigation in Nocturnal Insects Eric Warrant and Marie Dacke pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp239 The Role of Phytopathogenicity in Bark Beetle–Fungal Symbioses: A Challenge to the Classic Paradigm Diana L. Six and Michael J. Wingfield pppppppppppppppppppppppppppppppppppppppppppppppppppp255 Robert F. Denno (1945–2008): Insect Ecologist Extraordinaire Micky D. Eubanks, Michael J. Raupp, and Deborah L. Finke ppppppppppppppppppppppppppp273 The Role of Resources and Risks in Regulating Wild Bee Populations T’ai H. Roulston and Karen Goodell ppppppppppppppppppppppppppppppppppppppppppppppppppppppp293 Venom Proteins from Endoparasitoid Wasps and Their Role in Host-Parasite Interactions Sassan Asgari and David B. Rivers pppppppppppppppppppppppppppppppppppppppppppppppppppppppp313 Recent Insights from Radar Studies of Insect Flight Jason W. Chapman, V. Alistair Drake, and Don R. Reynolds ppppppppppppppppppppppppppp337 Arthropod-Borne Diseases Associated with Political and Social Disorder Philippe Brouqui ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp357 Ecology and Management of the Soybean Aphid in North America David W. Ragsdale, Douglas A. Landis, Jacques Brodeur, George E. Heimpel, and Nicolas Desneux pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp375 A Roadmap for Bridging Basic and Applied Research in Forensic Entomology by University of California - San Diego on 08/13/13. For personal use only. J.K. Tomberlin, R. Mohr, M.E. Benbow, A.M. Tarone, and S. VanLaerhoven pppppppp401 Annu. Rev. Entomol. 2011.56:21-40. Downloaded from www.annualreviews.org Visual Cognition in Social Insects Aurore Avargu`es-Weber, Nina Deisig, and Martin Giurfa pppppppppppppppppppppppppppppp423 Evolution of in the Lepidoptera Cerisse E. Allen, Bas J. Zwaan, and Paul M. Brakefield ppppppppppppppppppppppppppppppppp445 Forest Habitat Conservation in Africa Using Commercially Important Insects Suresh Kumar Raina, Esther Kioko, Ole Zethner, and Susie Wren pppppppppppppppppppppp465 Systematics and Evolution of Heteroptera: 25 Years of Progress Christiane Weirauch and Randall T. Schuh ppppppppppppppppppppppppppppppppppppppppppppppp487

viii Contents