Journal of Insect Physiology 84 (2016) 70–89

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Journal of Insect Physiology

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Review Insect-induced effects on plants and possible effectors used by galling and leaf-mining insects to manipulate their host-plant ⇑ David Giron a, , Elisabeth Huguet a, Graham N. Stone b, Mélanie Body c a Institut de Recherche sur la Biologie de l’Insecte, UMR 7261, CNRS/Université François-Rabelais de Tours, Parc Grandmont, 37200 Tours, France b Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom c Division of Plant Sciences, Christopher S. Bond Life Sciences Center, 1201 Rollins Street, University of Missouri, Columbia, MO 65211, United States article info abstract

Article history: Gall-inducing insects are iconic examples in the manipulation and reprogramming of plant development, Received 21 October 2015 inducing spectacular morphological and physiological changes of host-plant tissues within which the Received in revised form 21 December 2015 insect feeds and grows. Despite decades of research, effectors involved in gall induction and basic mech- Accepted 22 December 2015 anisms of gall formation remain unknown. Recent research suggests that some aspects of the plant Available online 23 December 2015 manipulation shown by gall-inducers may be shared with other insect herbivorous life histories. Here, we illustrate similarities and contrasts by reviewing current knowledge of metabolic and morphological Keywords: effects induced on plants by gall-inducing and leaf-mining insects, and ask whether leaf-miners can also Gall-inducing insects be considered to be plant reprogrammers. We review key plant functions targeted by various plant repro- Leaf-miners Plant manipulation grammers, including plant-manipulating insects and nematodes, and functionally characterize insect Effectors herbivore-derived effectors to provide a broader understanding of possible mechanisms used in host- plant manipulation. Consequences of plant reprogramming in terms of ecology, coevolution and diversi- fication of plant-manipulating insects are also discussed. Ó 2015 Elsevier Ltd. All rights reserved.

Contents

1. Introduction ...... 71 2. Induced effects in host-plants ...... 74 2.1. Altering plant morphology ...... 74 2.1.1. Induced cellular modifications...... 74 2.1.2. Possible targeted plant developmental pathways ...... 76 2.1.3. Patterns of diversification within galling lineages ...... 76 2.2. Controlling plant nutritional quality ...... 77 2.2.1. Improvement of nutrient concentrations ...... 77 2.2.2. Disruption of plant defense ...... 77 2.2.3. Multitrophic selection on gall induction traits ...... 78 2.3. Hijacking the plant signaling network ...... 78 3. Effectors used by insects to manipulate plants ...... 79 3.1. Effectors of gall-inducing insects ...... 79 3.2. Other insect derived effectors...... 80 3.2.1. Glucose oxidase ...... 80 3.2.2. ATP-hydrolyzing enzymes ...... 80 3.2.3. Calcium-binding proteins...... 81 3.2.4. Other candidates...... 81 3.3. Insect effectors and plant growth regulators...... 81 3.4. Microbial partners and plant manipulation in insect–plant interactions ...... 82 3.4.1. Insect symbionts and suppression of plant defense ...... 82

⇑ Corresponding author. E-mail address: [email protected] (D. Giron). http://dx.doi.org/10.1016/j.jinsphys.2015.12.009 0022-1910/Ó 2015 Elsevier Ltd. All rights reserved. D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 71

3.4.2. Insect microbial symbionts and impact on plant nutritional status and morphology ...... 82 3.4.3. Insect microbial symbionts and effectors encoded by horizontally transferred genes...... 82 3.4.4. Microbes and insect plant specialization ...... 83 4. Concluding thoughts ...... 83 Acknowledgements ...... 84 References ...... 84

1. Introduction et al., 2005). These strategies include associations with one or more symbiotic partners providing new metabolic pathways (Douglas, Nutrition is the cornerstone of most interactions between organ- 2009, 2013; Moran et al., 2008), symbioses in which plants have isms. With more than 4 million estimated species, insects are evolved food rewards specifically for insects (e.g. Heil and McKey, among the most significant evolutionary successes on Earth 2003), and/or intricate interactions that involve insect reprogram- (Novotny et al., 2002). The origin of this success can be directly ming of host-plant development, resulting in new structures bene- linked to the diversity of their feeding strategies, of which herbivory fiting the parasitic herbivore at the expense of the plant (Giron et al., is the most common (Schoonhoven et al., 2005; Slansky and 2013; Price et al., 1987; Stone and Schönrogge, 2003). Rodriguez, 1987). However, plant tissues are typically suboptimal Insect galls are structures composed of plant tissues that nutritionally, due to unbalanced ratios and/or low levels of key develop in response to stimuli produced by the gall-inducer, and nutrients and frequent requirement to detoxify plant defensive alle- present inducer-specific phenotypes and patterns of tissue differ- lochemicals (Schoonhoven et al., 2005). The ability of phytophagous entiation (Stone and Schönrogge, 2003). The need for induction arthropods to exploit plant resources requires them to employ a by another organism distinguished true galls from other structures suite of pre- and post-ingestive mechanisms to address the nutri- that have evolved to accommodate insects but which are under tional mismatch between what plants provide and what insects plant control – such as the domatia of myrmecophytes occupied require (Behmer, 2009; Raubenheimer et al., 2009; Schoonhoven by guarding ants (e.g. Raine et al., 2002). Galls are among the most

Fig. 1. Examples of plant manipulation by gall-inducing and leaf-mining insects. (a) Green-island induced by the leaf-miner Phyllonorycter joannisi (Lepidoptera, Gracillariidae) on maple leaf. (b) ‘Blister galls’ induced by a gall midge fly (unidentified species; Diptera, Cecidomyiidae) on honeysuckle leaf. (c) ‘Hazelnut gall’ induced by the gall midge fly Schizomyia vitiscoryloides (Diptera, Cecidomyiidae) on grape nodes. (d) ‘Tomato galls’ induced by the gall midge fly Janetiella brevicauda (Diptera, Cecidomyiidae) on grape flower buds. (e) Green-island (around a serpentoid mine) induced by the leaf-miner Lyonetia clerkella (Lepidoptera, Lyonetiidae) on a Prunus tree’s leaf. (f) ‘Woolly gall’ induced by the Cynipid wasp Callirhytis lanata (Hymenoptera, Cynipidae) on oak leaf. (g) ‘Bedeguar gall’ induced by the Cynipid wasp Diplolepis rosae (Hymenoptera, Cynipidae) on rose leaf bud. (h) ‘Tube galls’ and ‘pocket-like galls’ respectively induced by the gall midge fly Schizomyia viticola (Diptera, Cecidomyiidae) and the phylloxera aphid, Daktulosphaira vitifoliae (Hemiptera, Phylloxeridae), on grape leaf. (i) Green-island induced by the spotted tentiform leaf-miner Phyllonorycter blancardella (Lepidoptera, Gracillariidae) on apple-tree leaf. Credit photo: D. Giron (a) and M. Body (b–i). Table 1 72 Plant alteration by manipulating organisms. Comparison between leaf-mining insects, gall-inducing insects and gall-inducing nematodes for plant nutrient, defense, morphology and phytohormone alterations (selected publications). Credit photo: William Wergin and Richard Sayre (nematode), Mélanie Body (leaf-miner), Mélanie Body and Ryan Richardson (galling insect).

Leaf-mining insect Galling insect Root-knot nematode phytopathogen Nutrients Nutrition optimization Nutrition optimization Nutrition optimization  Alteration of source-sink relationship (Body et al., 2013;  Alteration of source-sink relationship (Compson et al., 2011;  Alteration of source-sink relationship (Kaplan et al., 2011; Giron et al., 2007) Larson and Whitham, 1991) Kyndt et al., 2013)  Control of sugar and amino acid composition (Body, 2013;  Control of sugar and amino acid composition (Dardeau et al.,  Control of mineral, starch, sugar and amino acid composition Body et al., 2013) 2015; Liu et al., 2007; Saltzmann et al., 2008; Stuart et al., (Nasr et al., 1980) 2012) Selective feeding Selective feeding Selective feeding

 Nutrient-rich cells (Body et al., 2015)  Nutritive tissue (Harris et al., 2006; Shorthouse and  Nutritive tissue (Caillaud et al., 2008; Favery et al., 2016) 70–89 (2016) 84 Physiology Insect of Journal / al. et Giron D.  Nutrient-rich tissues (Body et al., 2015; Scheirs et al., 2001) Rohfritsch, 1992) Defenses Defense inhibition Defense inhibition Defense inhibition  Phenolic compounds (Giron et al., unpublished)  Phenolic compounds (Liu et al., 2007; Stuart et al., 2012)  Phenolic compounds  Tannins (Ikai and Hijii, 2007)  Reactive Oxygen Species (ROS) (Dubreuil et al., 2007; Favery  Proteases (Liu et al., 2007) et al., 2016)  Volatiles (Tooker and De Moraes, 2007) Physical mechanisms  Vein-cutting (Whiteman et al., 2011) Morphology ? Induction of nutritive tissues (Harris et al., 2006; Stuart et al., Induction of giant cells at feeding site (Caillaud et al., 2008; Favery 2012) et al., 2016) Alteration of cell-walls at feeding site Alteration of cell-walls at feeding site Alteration of cell-walls at feeding site  Chemistry (Body, 2013)  Chemistry and morphology (Harris et al., 2006, 2010; Khajuria  Chemistry and morphology (Favery et al., 2016; Rosso et al., 2012) et al., 2013; Liu et al., 2007; Stuart et al., 2012) Regulation of stomata opening (Pincebourde and Casas, 2006) Induction of stomata formation (Nabity et al., 2013)? ? Formation of new vascular elements (Wool et al., 1999; Wool, ? 2005) Phytohormones Phytohormone accumulation/enhanced signaling Phytohormone accumulation/enhanced signaling Phytohormone accumulation/enhanced signaling  CKs (Body et al., 2013; Giron et al., 2007; Zhang et al., 2016)  CKs (Mapes and Davies, 2001b)  CKs (Kyndt et al., 2013; Rosso et al., 2012; Siddique et al., 2015)  SA (Zhang et al., 2016)  IAA (AUX) (Mapes and Davies, 2001a; Tooker and De Moraes,  AUX (Kyndt et al., 2013; Rosso et al., 2012) 2011a, 2011b)  GAs (Kyndt et al., 2013)  BRs (Kyndt et al., 2013) Phytohormone decrease/reduced signaling Phytohormone decrease/reduced signaling Phytohormone decrease/reduced signaling  ABA (Zhang et al., 2016)  ABA (Tooker and De Moraes, 2011a, 2011b)  SA (Favery et al., 2016; Kyndt et al., 2013)  JA (Zhang et al., 2016)  SA (Tooker and Helms, 2014)  JA (Ji et al., 2013)  JA (Tooker and Helms, 2014)  ET (Kyndt et al., 2013) Table 2 Effectors involved in plant manipulation. Potential effectors involved in plant manipulation (selected publications). Effectors for which functional data is available are shaded in gray. HGT: horizontal gene transfer. PCWDE: plant cell- wall degrading enzymes; see text for other abbreviations. Credit photo: William Wergin and Richard Sayre (nematode), Mélanie Body (leaf-miner, caterpillar and aphid), Mélanie Body and Ryan Richardson (galling insect). .Grne l ora fIsc hsooy8 21)70–89 (2016) 84 Physiology Insect of Journal / al. et Giron D. 73 74 D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 emblematic examples of plant manipulation by insects. By ‘repro- 2.1. Altering plant morphology gramming’ expression of the plant genome, the insect forces the plant to create specialized nutritional and sometimes protective 2.1.1. Induced cellular modifications resources that benefit the insect at the expense of the plant’s Gall-inducers manipulation of host-plant development results growth and reproduction. Gall induction involves hijacking of plant in complex tissue reorganization, sometimes effectively resulting cellular machinery and development, creating completely new in new plant organs (Mani, 1964; Harper et al., 2004; Rohfritsch, structures with features and functions of a novel plant organ 1992; Shorthouse et al., 2005a). In response to gall induction stim- (Fig. 1)(Mani, 1964; Shorthouse and Rohfritsch, 1992; Shorthouse uli from the ovipositing mother and/or her offspring, host tissues et al., 2005a; Stone and Schönrogge, 2003). Gall structures range usually dedifferentiate and gall development often involves a com- from highly complex and differentiated structures including nutri- bination of cell division (hyperplasia) and growth (hypertrophy) tive inner tissues and complex protective outer tissues (e.g. in cyni- (Carneiro et al., 2014, 2015; Dias et al., 2013; Oliveira and Isaias, pids, aphids, thrips and gall midges) to less dramatic structures 2010; Suzuki et al., 2015). Cell divisions occur in several planes, comprising nutritive tissues only (as in the Hessian fly Mayetiola increasing the number of cell layers and hence the thickness of destructor, whose open galls at the base of its host-plant are pro- the host tissues. In leaves, both the homogenization of the par- tected between the leaf sheaths). The Hessian fly shares with many enchyma and cell hypertrophy are common phenomena in gall for- other gallers the ability to induce a highly differentiated nutritive mation and are related to the modification of the mesophyll into tissue that provides the developing larva with a diet rich in nutri- nutritive and protective tissues (Mani, 1964; Moura et al., 2008; ents (Harris et al., 2006; Saltzmann et al., 2008). Nutritive tissues Oliveira and Isaias, 2010; Pincebourde and Casas, 2016; Price are both more nourishing and less well defended than are non- et al., 1987; Rohfritsch, 1992; Souza et al., 2000; Stone and gall tissues on the same plant and are a typical feature of many Schönrogge, 2003). Gall tissue differentiation can also involve gall-inducing organisms, including insects, mites, nematodes, fungi, changes in cell ultrastructure rather than hypertrophy and hyper- bacteria and viruses (Bronner, 1992; Favery et al., 2016; Harris plasia. For example, imaging studies of development of the nutri- et al., 2006; Mani, 1992; Oliveira et al., 2016; Pointeau et al., tive tissues of Hessian fly galls show nutritive cells to exhibit an 2013; Rohfritsch, 1992; Stone and Schönrogge, 2003). increase in cytoplasmic staining, in numbers of cellular organelles In insects, mechanisms underlying gall induction and growth (mitochondria, proplastids, Golgi, and rough endoplasmic reticu- are largely unresolved, driving a very active research area that is lum), along with development of numerous small vacuoles and the subject of many of the papers in this Special Issue. We suggest an irregularly shaped nucleus (Harris et al., 2006). that looking at similarities in the responses elicited by plant repro- Nutritive tissue can be very localized or more extensive, cover- grammers in a diversity of systems may identify key plant func- ing most of the inner surface in many closed galls (Shorthouse and tions that are targeted during plant manipulation. An overview of Rohfritsch, 1992). In some cases, immature stages actively feed on plant functions targeted by these reprogrammers (Table 1) and of a lining of nutritive tissues, pupating when all has been consumed. the insect herbivore-derived effectors that could possibly be In cynipid galls, the nutritive tissues are typically surrounded by a involved (Table 2) may facilitate inference of the stimuli and pro- hard schlerophyllous shell surrounding the larval chamber, with cesses involved in gall induction. We first review current knowl- these and other gall tissues supplied by vascular tissues connected edge of the effects on plants induced by leaf-mining and gall- to the vascular system of the host-plant (Stone et al., 2002). New inducing insects, highlighting ways in which leaf-miners can also sieve tubes (phloem elements) are usually formed below the inner be considered plant reprogrammers (Table 1). We then compare gall surface, supplying and enveloping the nutritive tissue, such as plant metabolic and morphological responses to plant- in galls induced by Geoica wertheimae aphids (Rohfritsch, 1992; reprogramming insects and nematodes and identify candidate Wool et al., 1999; Wool, 2005). insect effectors for plant manipulation (Table 2). We explore the Characteristics of nutritive cells vary depending on the family consequences of plant manipulation for the ecology, coevolution and species of gall-inducer, and can show differentiation between and diversification of plant-manipulating insects (Fig. 2). the inner ‘typical nutritive tissue’ on which the inducer feeds, and more peripheral ‘storage nutritive tissue’ (Bronner, 1992). Typical 2. Induced effects in host-plants features of nutritive cells induced by galling insects, and also root-knot nematodes, include endoreduplicated or hypertrophied Insects that manipulate plant development show strategies that nuclei and nucleoli, reduced and fragmented vacuoles, increased remodel the cell content and structure of plant tissues at their feed- number of cellular organelles (mitochondria, proplastids, Golgi, ing site (Fig. 1). These changes lead to demonstrably improved and rough endoplasmic reticulum), dense cytoplasm, and frequent nutritional value and/or nutrient access, and have been interpreted communications between cell layers and vascular tissues through as adaptations that address the mismatch between the nutrient sta- numerous/enlarged plasmodesmata (Bronner, 1992; Dardeau tus of unmodified host-plant tissues and the herbivore’s require- et al., 2014a; Favery et al., 2016; Harper et al., 2004; Harris et al., ments (Table 1)(Body, 2013; Body et al., 2013; Dardeau et al., 2006; Isaias and Coelho De Oliveira, 2012; Jones and Payne, 2014a; Harris et al., 2006; Liu et al., 2007; Moura et al., 2008; 1978; Oliveira et al., 2016; Rodiuc et al., 2014; Schönrogge et al., Oliveira and Isaias, 2010; Souza et al., 2000). Induction of nutritive 2000). Additionally, cells usually have thin walls because of the tissues is a key feature of many gall-inducing insects (Harris et al., inhibition of cell-wall fortification and expansion. For example, 2006; Rohfritsch, 1992; Stone and Schönrogge, 2003). The evolution within Hessian fly (M. destructor) feeding sites, genes involved in of nutritive tissues may be associated with the development of the biosynthetic pathways for cell-wall components (such as cellu- additional tissues that partially or wholly surround the gall- lose synthase) and loosening (such as xyloglucan endotransgluco- inducer. These additional tissues have been hypothesized to protect sylase (XET), b-expansin, endo-1,4-b glucanases, pectinesterase, the inducer from abiotic stress and/or natural enemies, though (as and polygalacturase) are downregulated (Liu et al., 2007; highlighted for Hessian fly above), not all galls have them (Harris Khajuria et al., 2013). Variations in cell-wall composition (espe- et al., 2006; Pincebourde and Casas, 2016; Stone and Schönrogge, cially polysaccharides) during gall development have just started 2003). Similarly, the degree of nutritive tissue differentiation also to be explored, highlighting the functionality of cell-walls in gall varies among gall-inducers, being most obvious where the insects ontogenetic steps and their role in insect nutrition or plant resis- actively consume the tissues (e.g. cynipid and chalcid wasps) rather tance (Carneiro et al., 2014; Khajuria et al., 2013). Gall parenchyma than feeding on them suctorially (e.g. aphids). cells generally show reduced intercellular spaces, characteristic of D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 75

(A)

Free-feeding acve herbivore

1. Nutrition 1. Enemies 2. Abiotic factors Sedentary surface-feeding insects

Leaf-miners 1. Nutrition

Differenal plant growth 1. Nutrition causes feeding depressions 2. Enemies 1. Enemies 3. Abiotic factors 2. Abiotic factors 3. Nutrition

Gall-inducers Gall-inducers

HYPOTHESIS #1 HYPOTHESIS #2

(B)

Free-feeding acve herbivore

1. Nutrition

1. Abiotic factors 1. Enemies 2. Nutrition 2. Abiotic factors 3. Enemies Ancestral plant-manipulator 3. Nutrition

1. Enemies 2. Abiotic factors 3. Nutrition

Leaf-miners Leaf-miners Gall-inducers Gall-inducers ?

HYPOTHESIS #1 HYPOTHESIS #2 HYPOTHESIS #1

Fig. 2. Origin of the gall-inducing habit. (A) The two routes to gall formation from free-feeding active herbivores suggesting leaf-miners as an intermediate primitive form of endophytophagy (adapted from Price et al. (1987)). (B) Possible routes for the evolution of plant-manipulating insects. Leaf-miners and gall-inducers may have evolved independently (dashed arrows), finding similar solutions to face analogous threats (adaptive convergence) or they may have evolved from a common plant-manipulating ancestor (solid arrows) leading to shared ancestral plant manipulation strategies (homologies). Possible selective factors are listed in possible order of importance for immediate impact on herbivore fitness. Credit photo: M. Body. 76 D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 young and fast-growing tissues. Such lack of intercellular spaces nutritive tissues, in which chromosomes are duplicated without indicates low potential for gas exchange and consequent reduced cell division, hence increasing their nucleic acid content (Harper photosynthetic capacity in some galls (Carneiro and Isaias, 2015; et al., 2004; Schönrogge et al., 2000). Other hypotheses under cur- Moura et al., 2008). rent investigation consider that development of at least some galls Gall tissues act as a strong resource sink for photo-assimilates, involves plant reproductive pathways. If this were the case, the and can be associated with massive changes in plant growth, meta- vegetative tissues must obtain reproductive competency and some bolism, and investment (Allison and Schultz, 2005; Anderson and floral and/or fruit identity traits must be expressed (Schultz, per- Harris, 2006, 2008; Bagatto et al., 1996; Fay et al., 1993; Larson sonal communication; Ferreira and Isaias, 2014; Von Aderkas and Whitham, 1991; Raman et al., 2006; Rehill and Schultz, 2003, et al., 2005). By creating appropriate signals in gall tissues, gall- 2012), linked directly to the feeding site and hence growth of the inducers may take advantage of existing suites of plant develop- gall-inducer (Compson et al., 2011; Harris et al., 2006). Induced mental pathways. The ‘galls as seeds’ and ‘galls as ectopic fruits’ changes in organization of the plant vascular tissues facilitate nutri- hypotheses may emerge as useful hypotheses for the identification ent translocation and insect access to host-plant nutrients (Wool of candidate plant existing pathways targeted by gall-inducing et al., 1999). Nutritive cells also have an intense metabolic activity insects. controlled by the larvae, resulting in the up-regulation of protein and/or sugar synthesis directly at the insect’s feeding site 2.1.3. Patterns of diversification within galling lineages (Bronner, 1992; Giron et al., 2007; Larson and Whitham, 1991; A striking feature of gall morphologies is that while some Stone and Schönrogge, 2003). Modified cell-wall morphology and aspects are conserved within lineages, others can be very different composition may help insects to feed because plant cell contents even in closely related species. In cynipid gallwasps, for example, break down and move from cell to cell through compromised many species share highly similar inner nutritive tissues on which cell-walls (Bronner, 1992; Harris et al., 2006; Rohfritsch, 1992). This the larvae feed. In contrast, outer gall tissues are often very differ- process shows a contrast in resistant and susceptible strains of ent between species, as well as highly diagnostic (Bailey et al., wheat attacked by Hessian fly; cytological studies show cell-wall 2009). While we do not yet know which mechanisms underlie breakdown in susceptible plants (Harris et al., 2006) and fortifica- the development of either of these tissue types, we can hypothe- tion of the cell-wall in resistant plants (Harris et al., 2010). The size that when revealed the genes responsible will show contrast- breakdown of nutritive cells in the uppermost layer of the nutritive ing patterns of selection – stabilizing in the case of nutritive tissue has been observed for a number of gall-inducing insects tissues, and diversifying in the case of enemy-driven diversification including cynipid gallwasps and cecidomyiid gall midge larvae of defensive structures (Bailey et al., 2009). The interaction (Bronner, 1992; Rohfritsch, 1992). Cell harvest in the nutritive tis- between gall location and gall induction has also yet to be studied sue by insects most likely results from a combination of increased in detail for most galler radiations. It is clear that whatever mech- permeability of plant cell-walls, enlarged plasmodesmata, mechan- anisms are used by gall-inducers, the location of the gall on the ical action of larval mouthparts, high turgor pressure in the nutri- plant is not a strong constraint to gall induction: both cynipid gall- tive cells, and possibly secretion and injection of proteases into wasps and cecidomyiid gall midges provide examples of species cells by gall-inducing insects (Harris et al., 2006). radiations on a single host taxon in which there have been frequent As far as we know, while leaf-miners can influence the nutritive shifts between gall locations (such as leaf, bud, fruit, flower) on the quality of host-plant tissues (see below), no morphologically dis- same plant host (Cook et al., 2002; Joy and Crespi, 2007). We do tinct nutritive tissue has yet been found in insect mines. There is know that maternal oviposition can be highly site specific – in no obvious tissue differentiation involving hyperplasia or hyper- the case of rose gallwasps, to particular leaves in a rose bud trophy of cells around mining insect larvae. Morphological studies (Shorthouse et al., 2005b). It is thus probable that for cynipids at on mines remain scarce (e.g. Body et al., 2015; Jeanneau, 1971; least, gall traits are the result of both maternal behavior (oviposi- Melo De Pinna et al., 2002; Scheirs et al., 2001)(Table 1) and this tion site selection, number of eggs laid) and induction stimuli pro- remains an area for further investigation. duced by the larva (Stone and Schönrogge, 2003). We also know that when forced to oviposit on atypical parts of their host-plant, 2.1.2. Possible targeted plant developmental pathways at least some gallwasps can still induce galls (Folliot, 1964). In Plant galls can be viewed as novel plant organs whose develop- stylet-feeding gall-inducers, foundress and nymph feeding behav- ment is triggered by induction of existing plant developmental ior determine gall structure and development. Patterns of diversi- pathways in unusual (ectopic) places and/or combinations fication in some stylet-feeding galling lineages suggest (Harper et al., 2004). Galls often contain plant tissue types that evolutionary responses to selection for enhanced nutrition are found nowhere else on the plant – such as the brightly colored (Crespi and Worobey, 1998; Inbar et al., 2004). There is strong tissues, spines and extrafloral nectaries induced by some cynipid empirical evidence that ovipositing females can play a role in gallwasps on oaks (Stone and Schönrogge, 2003). The same gall- gall-induction due to specific host selection behaviors (e.g. gall- inducers are also able to cause the development of tissues that wasps: Atkinson et al., 2002; Hessian fly: Harris et al., 2003), show very high investment in metabolites: in oak cynipid galls, and/or to the delivery of gall-induction stimuli during oviposition this includes heavy investment in nucleic acids and fatty acids in to initiate the process of plant tissue dedifferentiation (e.g. saw- the internal nutritive tissues on which the gall-inducer feeds flies: Roininen et al., 2005; cynipids: Sliva and Shorthouse, 2006). (Harper et al., 2004; Schönrogge et al., 2000; Stone et al., 2002) Females not only decide where to lay the eggs but also how many and high levels of (metabolically cheap) tannins in outer gall tis- eggs to lay in one place (Atkinson et al., 2002, 2003; Bailey et al., sues as putative antiherbivore defenses (Allison and Schultz, 2009). Assuming that induction stimuli contributed by each egg/ 2005; Rehill and Schultz, 2012). In several oak cynipid galls, devel- larva are important for determining signal strength for induction opment is associated with expression of biotin carboxylase carrier and sink strength for the plant, maternal oviposition behaviors protein (BCCP), a component of the triacylglycerol lipid synthesis are key for the gall induction and larval food provisioning pro- pathway that is associated with lipid food storage in seeds of Bras- cesses. We propose that the observed diversity in gall structures sica napus. This led to proposal that gallwasps may cause novel can be brought about by changes in inducer behavior such as expression of seed developmental pathways in gall induction changes in the time and/or place in which otherwise similar stim- (the ‘galls as seeds’ hypothesis; Harper et al., 2004; Schönrogge uli are applied as well as in evolution in the effectors they use to et al., 2000). Oak cynipid galls also show endoreduplication in control plant development. D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 77

2.2. Controlling plant nutritional quality carbon-containing compounds to nitrogen-containing compounds (Zhu et al., 2008), the increase in amino acids resulting in better 2.2.1. Improvement of nutrient concentrations food quality for Hessian fly larvae. The ability to alter the physiological state of plant tissues, par- In most cases, gall-inducing insects are thought to have an ticularly of the cells nearest to the feeding site, has been well advantage over non-galling insects because the gall-inducer con- described for root-knot nematodes and a range of gall-inducing centrates nutrients in the gall, making it a better food source than arthropods (Abrahamson and Weis, 1987; Bronner, 1983; equivalent ungalled plant tissue (Abrahamson and Weis, 1987; Dardeau et al., 2015; Favery et al., 2016; Harper et al., 2004; Bronner, 1983; Hartley, 1998; Hartley and Lawton, 1992; Mani, Hartley, 1998; Hartley and Lawton, 1992; Larson and Whitham, 1964; Price et al., 1986, 1987; Rohfritsch and Shorthouse, 1982; 1991; Mani, 1964; Nabity et al., 2013; Nasr et al., 1980; Shannon and Brewer, 1980; Stone and Schönrogge, 2003; Stone Rohfritsch, 1988; Schönrogge et al., 2000; Shorthouse, 1986; et al., 2002). However, despite the fact that several studies support Wool et al., 1999). Nutritive tissues are kept in an active metabolic Price et al.’s (1987) original nutrition hypothesis, gall-inducing state by the galling insect and tend to contain high levels of nutri- insects do not always benefit from high nutrient concentrations ents including minerals, lipids, proteins, amino acids, sugars and/or per se (Hartley, 1998; Hartley and Lawton, 1992). In its broadest starch (Bronner, 1992; Liu et al., 2007; Nasr et al., 1980; Saltzmann form, the nutrition hypothesis for the adaptive nature of galls et al., 2008; Stuart et al., 2012). Enhanced nutritional value of gall states that galling insects control nutrient levels in galls for their tissues surrounding larval chambers in closed galls results from own benefit (Diamond et al., 2008; Hartley, 1998; Hartley and intense proteosynthesis (mostly structural and enzymatic pro- Lawton, 1992). Thus, the thistle gall-inducing fly Urophora cardui teins) and, at the same time, proteolysis resulting in an accumula- and two cynipid galling-wasps (Neuroterus quercus-baccarum and tion of soluble amino acids and a net increase of soluble nitrogen Andricus lignicola) benefit from manipulating their host-plants in (Koyama et al., 2004; Nabity et al., 2013; Palct and Hassler, a way that prevents nitrogen levels from increasing in the galls 1967). These products may also come directly from the host- (Gange and Nice, 1997; Hartley and Lawton, 1992). In these spe- plant through the vascular system (Bronner, 1983). Additionally, cies, nitrogen increase reduced insect survival rates. significant active transport of sugars toward the insect’s feeding Among insects, manipulation of the nutritional value of plant site is frequently observed due, at least partially, to increased tissues is not restricted to gall-inducers; the leaf-miner caterpillar invertase activity (Larson and Whitham, 1991; Nabity et al., Phyllonorycter blancardella modifies nutrient profiles in mined 2013; Rehill and Schultz, 2003). Glucose in excess can be trans- apple-tree leaf tissues (Body, 2013; Body et al., 2013; formed into lipids and in cynipid galls numerous lipid droplets Engelbrecht et al., 1969; Giron et al., 2007; Kaiser et al., 2010). This can be observed in nutritive cells nearest to the larval chamber manipulation allows the insect to maintain nutrient-rich green tis- (Bronner, 1983). Starch is also accumulated in nutritive storage tis- sues (sugars, free and protein-bound amino acids) (‘green-island’ sues in cynipid galls and directly in the nutritive tissue of cecido- phenotype; Fig. 1) and to create an enhanced nutritional microen- myiid galls due to lower amylase activity (Bronner, 1992). vironment in fallen leaves, which are otherwise degrading (Body, Finally, excess of sugars may lead to a cascade of effects including 2013; Body et al., 2013; Giron et al., 2007). Further evidence of the up-regulation of anthocyanin synthesis explaining why some plant manipulation by leaf-mining insects comes from the obser- galls develop red coloration (Arnold et al., 2012; Belhadj et al., vation that radioactively labeled nutrients are preferentially trans- 2008; Connor et al., 2012; Inbar et al., 2010). Examples of enhanced ported and accumulate in the feeding area, as first highlighted by nutritional value of transformed plant tissues include galls induced Mothes and coworkers in the 1960s. This suggests that insect- by the cynipid wasp Neuroterus quercusbaccarum on oak and the derived effectors create a new source-sink relationship, thus caus- Daktulosphaira vitifoliae phylloxera on grape (Bronner, 1992; ing nutrient mobilization and accumulation at attack sites to feed Hartley, 1998; Kovácsné-Koncz et al., 2011; Nabity et al., 2013; insect metabolic needs (Mothes and Engelbrecht, 1961). Warick and Hildebrandt, 1966; Witiak, 2006). Insects inducing open galls are also able to significantly 2.2.2. Disruption of plant defense improve the nutritional quality of their feeding site. Infestation To maximize their fitness, herbivorous insects also need to by the galling insect Phloeomyzus passerinii triggers the accumula- manipulate and reduce plant defensive responses (Hartley, 1998; tion of both free and protein-bound amino acids at the feeding site, Hartley and Lawton, 1992; Price et al., 1986, 1987). Such ability the strength of the mobilizing sink being more pronounced when to alter plant defense expression has been demonstrated in several soil fertilization is reduced (Dardeau et al., 2015). The Hessian fly gall-inducing insect lineages. Phenolic compounds, for example, M. destructor alters the flow of nutrients in infested plants, result- are substantially lower in tissues close to the insect feeding site ing in improved food quality (Harris et al., 2006; Liu et al., 2007; and accumulate at the periphery of host-plant tissues infected by Saltzmann et al., 2008; Stuart et al., 2012). Evidence for increased P. passerinii and six Pontania sawfly species (Abrahamson and nutrient flow comes from changes in plant growth (Anderson Weis, 1987; Dardeau et al., 2014b; Nyman and Julkunen-Tiitto, and Harris, 2006, 2008) and the strong up-regulation of genes 2000). This result has also been shown for tannins that are essen- encoding various transporter proteins, including general sugar tially absent from nutritive tissues in cynipid wasp galls (Andricus transporters, glucose transporters, a myo-inositol transporter, and Trigonaspis spp.) in comparison to surrounding oak leaf tissues, ammonium transporters, and amino acid transporters (Liu et al., though present at very high levels in outer non-nutritive tissues 2007). Further evidence for improved food quality comes from (Allison and Schultz, 2005; Ikai and Hijii, 2007; see also Hartley, the strong up-regulation of genes involved in nutrient metabolism, 1998). The Hessian fly M. destructor has also been shown to cope including (i) genes involved in carbohydrate degradation such as with plant defenses by hijacking phenylpropanoid pathways in a-glucosidase and invertase; (ii) genes in glycolysis and the citric wheat. Indeed, the down-regulation of five out of the seven pro- acid cycle such as enolase, pyruvate dehydrogenase, and oxidore- tease inhibitor genes and many genes involved in the phenyl- ductases; and (iii) genes involved in amino acid synthesis such as propanoid pathway of the host-plant leads to lower aspartate aminotransferase and methionine synthase (Liu et al., concentrations of chalcone, flavonoids, isoflanoids and lignin at 2007). These alterations indicate that excess imported carbohy- the insect feeding site (Liu et al., 2007). These modifications are drates are degraded and converted into intermediates for amino favorable to Hessian fly development as many of these acid synthesis (Liu et al., 2007). This observation is consistent with phenylpropanoids may be toxic to insects (Stuart et al., 2012). the finding that Hessian fly attack causes a dramatic shift from For example, isoorientin, an abundant flavonoid in wheat, is toxic 78 D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 to corn earworm larvae, Helicoverpa zea (Widstrom and Snook, sequestering phenolics and tannins in the surrounding gall tissues 1998). Most researches have focused on insect strategies to coun- to repel generalist herbivores (Abrahamson et al., 1991; Allison teract plant chemicals including excretion, sequestration and and Schultz, 2005; Carneiro et al., 2014; Hartley, 1992; Ikai and degradation of phytotoxins. However, few examples have consid- Hijii, 2007; Mang et al., 2011; Rehill and Schultz, 2012). Plant phe- ered the direct modulation of plant metabolism by insects as a nolic accumulation may also be an adaptive way to sequester way to circumvent plant defenses at source. As a result, the mech- excess carbon that has accumulated in the gall (Arnold et al., 2012). anisms by which host defense levels are manipulated remain to be Galls are damaged by two groups of herbivores (i) those that demonstrated in any insect gall-inducer. specifically target gall tissues, often deliberately killing the gall- Modulation of plant secondary metabolism also occurs in leaf- inducer (such as the tortricid moths Pammene amygdalana and P. mining insects. For example, mining of apple leaves by the leaf- gallicola; Schönrogge et al., 1995; see also Abe, 1995, 1997), and miner P. blancardella appears to prevent mobilization by the tree (ii) those, such as some leaf-feeding caterpillars, that essentially of its main phenolic defense compounds (dihydrochalcone and fla- consume gall tissues accidentally, while feeding on plant parts on vonol) (Giron et al., unpublished data). While naturally senescing which the gall develops (Ejlersen, 1978). Gall inhabitants can also control leaves displayed a two-fold increase of these defensive suffer high mortality through attack by fungi (e.g. Stone et al., compounds, levels in tissues of miner-inhabited leaves remained 1995; Taper et al., 1986). While in some gall-inducers higher tan- stable and low. The dihydrochalcone phloridzin – the predominant nin levels are correlated with higher fitness (Rehill and Schultz, secondary compound of apple leaves – deters aphids (Dreyer and 2012), there is also some evidence that aphids in high tannin galls Jones, 1981; Schoonhoven and Derksen-Koppers, 1976) and beetles also have high levels of protective antioxidants to cope with a high (Fulcher et al., 1998) and inhibits the biosynthesis of the insect tannin environment. Two hypotheses have been advanced for such molting hormone ecdysone (Mitchell et al., 1993). Down- high tannin levels. One is that tannins serve as anti-feedants to regulation of this biosynthetic pathway may therefore benefit the reduce attack by generalist herbivores or to protect galling insects leaf-miner. The intimate association with the host-plant and the from parasitoids, while a second is that tannins serve to reduce important nutritional constraints associated with the endophy- mortality imposed by fungi (Carneiro et al., 2014; Cornell, 1983; tophagous lifestyle shared by most gall-inducers and all leaf- Schultz, 1992; Taper and Case, 1987; Taper et al., 1986; Wilson miners may have led to selection on each of these trophic groups and Caroll, 1997). Evidence to date shows that high tannin levels to evolve strategies to disrupt plant defense. benefit survival of cynipid gallwasps, while there is little evidence that high tannin levels exclude specialist gallivores, which can 2.2.3. Multitrophic selection on gall induction traits cause high mortality even in galls with very high tannin levels The nutritive tissues discussed above are a fundamental compo- (Schönrogge et al., 1995). It remains possible that high tannin nent of most insect galls. The non-nutritive tissues of many of the levels may confer protection against generalist herbivores, causing more complex galls seem to have no direct role in galler nutrition, them to avoid feeding on plant parts with gall-induced high tannin and hypotheses for their evolution are generally of two kinds (Price levels. There is evidence that some galling aphids can induce host et al., 1987; Stone and Schönrogge, 2003): (i) better protection volatiles that repel large vertebrate herbivores (Rostas et al., 2013). against unfavorable abiotic conditions (the microenvironment The important point is that in either case, gall-inducers in a range hypothesis), (ii) improved protection from attack by natural ene- of taxa can induce high tannin levels in external gall tissues. While mies and infestation by pathogens (the enemy hypothesis) (Fig. 2). evidence points to a defensive selective advantage for such manip- Gall tissues commonly harbor inhabitants in addition to the ulation in some cases, high tannin levels could indicate the role of gall-inducer, including (from the gall-inducer’s perspective) harm- the gall as a strong sink for host-plant nutrients, rather than always ful pathogens, gallivores (herbivores that specialize in eating gall conferring a direct advantage (Rehill and Schultz, 2012). High tissues), specific parasitoids or predators, and commensals (such levels of phenolics may also have indirect benefits for the plant- as inquilines) (Raman et al., 2005). These trophic divisions are manipulating insects by stimulating cell growth through an not absolute, because some predators and parasitoids also feed increase of auxin levels thus contributing to cell redifferentiation on gall tissues (Stone et al., 2002). Gall-inducing insects not only in galls (Carneiro et al., 2014; Oliveira et al., 2016). need to extract nutrients from their host-plant and counteract Just as selection may have shaped gall traits that protect the plant defenses but they also need to escape mortality imposed inducer, we might also expect other gall inhabitants to have by these other gall inhabitants, as well as natural enemies (such evolved some ability to modify gall tissues to their advantage. as insectivorous birds and small mammals) living outside the gall Some cynipid inquilines can indeed significantly influence gall (Stone and Schönrogge, 2003). It follows that given the ability of morphology, producing tougher galls that are likely to reduce gall-inducers to manipulate plant development, they should have attack rates by their own parasitoid natural enemies (Brooks and evolved the ability to induce gall tissue traits that confer protection Shorthouse, 1998). against these natural enemies (Stone and Schönrogge, 2003; Bailey et al., 2009). 2.3. Hijacking the plant signaling network With the general exception of galls induced by eriophyiid mites, most arthropod-induced galls are attacked by insect and/or verte- Signaling pathways involved in plant defense against insects are brate natural enemies. The enemy hypothesis states that much of known to be complex and ultimately lead to the synthesis of many the complexity and structure of gall tissues that are not directly different secondary metabolites (Pieterse and Dicke, 2007). The associated with inducer nutrition has evolved to exclude predators plant hormones salicylic acid (SA), jasmonic acid (JA) and ethylene and parasites (Price et al., 1987; Stone and Schönrogge, 2003). In (ET) have emerged as key players in the regulation of signaling net- oak cynipid galls, several gall structural traits have been shown works involved in these responses (Van Peocke and Dicke, 2004; not only to reduce enemy attack rates within species, but also to Von Dahl and Baldwin, 2007). Other plant hormones including structure the communities of natural enemies (Bailey et al., abscissic acid (ABA), gibberellins (GA), auxins (AUX) and cytokinins 2009). Defense can also be chemical rather than physical. While (CK) have also been reported to play a role in plant defensive interior gall tissues on which the inducer feeds are very low in responses, but are reported in fewer studies. Mimicry or manipula- secondary plant toxins (as noted above), outer gall tissues often tion of these phytohormones is one route towards insect control of contain high levels of phenolic compounds and it has been plant development (Giron et al., 2013). Recent reviews and papers proposed that the galling insect derives some benefit from actively nicely address the role played by phytohormones in gall induction D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 79 processes and their potential role in the evolution of the gall- when senescence occurs during the autumn (Body, 2013; Body inducing habit (Bartlett and Connor, 2014; Giron and Glevarec, et al., 2013; Giron et al., 2007). More globally, this leaf-miner leads 2014; Tooker and Helms, 2014). to strong reprogramming of plant phytohormonal balance, associ- Because many galls grow via hypertrophy and/or hyperplasia, ated with increased nutrient mobilization, inhibition of leaf senes- attention has focused on phytohormones that influence cell growth cence and mitigation of plant direct and indirect defense (Zhang and division, such as AUX and CKs (Bartlett and Connor, 2014; et al., 2016). Davies, 2004; Straka et al., 2010; Tooker and Helms, 2014; Tooker and De Moraes, 2011a; Yamaguchi et al., 2012). Several 3. Effectors used by insects to manipulate plants studies show that gall-inducing insects such as the Hessian fly M. destructor and the goldenrod elliptical-gall caterpillar Gnori- Although insect-induced galls are cited as iconic examples of moschema gallaesolidaginis, are able to induce indole-3-acetic acid extended phenotypes (Dawkins, 1982), in which plant tissue devel- (IAA) accumulation at the initiation site (Tooker and De Moraes, opment is mainly controlled by insect genes, insect effectors 2011a, 2011b; Zhu et al., 2010, 2011). IAA is the main AUX in plant involved in gall induction are only starting to be characterized tissues and is well known to cause plant cells to grow and divide; and basic mechanisms of gall formation are unknown. Several lines therefore, increase of IAA could play a role in generating the nutri- of evidence indicate that effectors secreted by the ovipositing tive cells at larval feeding sites. Studies on the pteromalid wasp mother or her gall-inhabiting offspring are indeed involved in gall Trichilogaster acacialongifoliae, the psyllid Pachypsylla celtidis and induction. First, in some cases the site of gall induction differs from the tephritid fly Eurosta solidaginis report high concentrations of the feeding sites of the gall-inducing insects suggesting a maternal CKs in galls (Dorchin et al., 2009; Mapes and Davies, 2001a, effect (Matsukura et al., 2009; Sopow et al., 2003). Secondly, appli- 2011b; Straka et al., 2010) – and particularly trans-Zeatin (tZ) in cation of extracts prepared from gall-inducing insects can induce the case of the maize orange leafhopper galler Cicadulina bipunc- physiological or morphological changes reminiscent of gall induc- tata (Tokuda et al., 2013). Selective elevation of tZ concentration tion (Schönrogge et al., 2000; Yamaguchi et al., 2012 and refer- may change the AUX:CKs ratio, critically affecting cell division pat- ences herein). Many galling insects at least have the potential to terns and tissue differentiation of plants and potentially playing a deliver effectors precisely to plant tissues from salivary glands key role in the development and maintenance of galls (Schaller using their mouthparts, or venom glands using ovipositors et al., 2015; Yamaguchi et al., 2012). Increased CK levels can also (Stuart et al., 2012; Vårdal, 2006). favor nutrient translocation toward the insect’s feeding site and Initial pioneering experiments suggesting that insect effectors delay senescence by increasing the activity of extracellular inver- could be involved in plant manipulation involved applying insect tase (Lara et al., 2004; Walters and McRoberts, 2006; Walters oral secretions to plants or plant products and determining their et al., 2008). Indeed, several studies show that extracellular inver- impact on plant defense suppression (Bartlett and Connor, 2014; tases are induced in various plants by biologically relevant concen- Kahl et al., 2000; Lawrence et al., 2007) and the subsequent conse- trations of CKs (Ehneß and Roitsch, 1997; Godt and Roitsch, 1997). quences on insect performance (Consales et al., 2012). Insect The latter work also found that hexose transporters were co- extracts were also tested for their capacity to induce morphological induced with extracellular invertase by elevated levels of CKs. changes in plants (e.g. Yamaguchi et al., 2012) or physiological sig- The coordinated up-regulation by CKs of the two functionally natures in suspensions of host-plant cells (Schönrogge et al., 2000). linked key enzymes of an apoplasmic phloem unloading pathway Alternatively, ablation of caterpillar salivary glands was also devel- may account for the transport of nutrients to CK-treated tissue oped to determine the role of saliva in insect–plant interactions and the accumulation of nutrients at attack sites first highlighted (Musser et al., 2006). Since then, several insect herbivore effectors by Mothes and coworkers in the 1960s. Other benefits gained from have been characterized (Table 2) but their modes of action in the higher levels of IAA or CKs are linked to their negative crosstalk plant are, in most cases, unknown. with JA, thus lowering JA-mediated induced defenses (Erb et al., Work on insect herbivore-derived effectors involved in plant 2012; Tooker and De Moraes, 2011a, 2011b; Tooker and Helms, manipulation is an emerging field (e.g. Acevedo et al., 2015; 2014; Ueda and Kato, 1982). This may also account for lower levels Guiguet et al., 2016; Zhao et al., 2016). Here, we present function- of ABA and SA frequently observed in galls (Tooker and De Moraes, ally characterized effectors from insects across a range of feeding 2009, 2011a, 2011b; Tooker et al., 2008). Finally, interfering with modes, as relatively few data are so far available for leaf-miners CK and AUX composition within host-plant tissues could also and galling insects. We predict that –omics approaches (genomics, explain anthocyanin accumulation associated with some galls transcriptomics, metabolomics) will lead to rapid increases in data and cause the striking red coloration frequently associated with for both model (Hessian fly, root knot nematode) and non-model gall induction (Connor et al., 2012; Inbar et al., 2010; Lewis et al., gall-inducers and other herbivory modes. Effectors functionally 2011; Russo, 2007; Stern et al., 2010; White, 2010). characterized in other plant-parasitic systems (but also in animal Maybe the best example of similarities between gall-inducing parasites – see Guiguet et al., 2016) may be potentially of value and leaf-mining insects comes from data on phytohormones. Sev- in deriving mechanistic hypotheses for insect reprogrammers of eral leaf-miner species, such as P. blancardella, Stigmella argyropeza plant development. and S. argentipedella, display ‘green-islands’ (photosynthetically active green patches in otherwise senescent leaves; Fig. 1) around 3.1. Effectors of gall-inducing insects mining caterpillars on yellow leaves (Body et al., 2013; Engelbrecht et al., 1969; Giron et al., 2007; Gutzwiller et al., 2015; Kaiser et al., To date, Hessian fly is the only gall-inducing insect for which 2010; Walters et al., 2008; Zhang et al., 2016) and show the ability the genome and salivary gland transcriptome and proteome are to modify phytohormonal profiles in mined leaf tissues of their published (Chen et al., 2008, 2010a; Zhao et al., 2015). The genome host-plant (Body et al., 2013; Engelbrecht et al., 1969; Giron provided evidence for hundreds of transcripts encoding candidate et al., 2007; Kaiser et al., 2010; Zhang et al., 2016). For example, effectors (Zhao et al., 2015). Genome sequencing and map-based CK concentrations of mined apple-tree tissues were shown to be cloning identified four candidate effectors, the Avirulence (Avr) higher than in unmined areas (Body et al., 2013; Giron et al., effector genes (Aggarwal et al., 2014; Zhao et al., 2015, 2016). For 2007; Zhang et al., 2016). Similarly to gall-inducers, the manipula- each of these, loss-of-function mutations permit the insect to tion of the plant CK content by P. blancardella allows the insect to escape the effector-triggered immunity (ETI) elicited by the corre- create nutrient-rich tissues favorable to its development even sponding, Avr-specific, resistance (R) gene (Harris et al., 2015). 80 D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89

RNA-interference-knockdown of the gene (vH13) encoding one of leaf-mining species allowing comparative approaches that may the effectors confirmed that knockdown of that gene allows larvae lead to the identification of convergent mechanisms involved in to survive on H13-resistant plants (Aggarwal et al., 2014). This sug- these interactions. Recently, a metatranscriptome of fig flowers gests that the vH13-encoded protein is an Avr-encoded effector, a allowed the identification of potential candidate effectors pro- protein that elicits ETI when secreted into plant cells that harbor duced by fig wasps. Among the highlighted candidates are proteins a corresponding R gene. The specific functions of vH6, vH9, vH13 such as icarapin, serine proteases, acid phosphatase, lipase, chy- and vH24 are not currently known and functional studies of the motrypsin and metalloproteinase that have already been identified four Avr effector candidates are now underway. The vH24- as venom components in other hymenopteran species (Martinson encoded effector possibly counteracts the protein kinase activities et al., 2015). Whether these candidates actually play a role in gall involved in the phytohormone signaling that is associated with formation awaits functional analyses. However, transcriptomic biotic stress (Zhao et al., 2016) while vH6 and vH9 are suspected and proteomic analyses do not always reveal the full set of effec- to contain F box domains and leucine-rich repeats that are known tors used by insects to attack their host-plants (Guiguet et al., to mediate protein-protein interactions involved in the regulation 2016; Zhao et al., 2016) requiring complementary tools such as of hormonal signaling, plant development and plant defense genomic and classical genetic approaches to capture the entire (Zhao et al., 2015). set of effectors used in plant-insect interactions. Based on transcriptomic and proteomic analyses, a small per- centage of Hessian fly putative secreted proteins showed similarity 3.2. Other insect derived effectors to proteases and protease inhibitors also expressed in the gut, and to lipase-like proteins (Stuart et al., 2012). One lipase-like gene was 3.2.1. Glucose oxidase shown to be highly expressed in salivary glands of first instar lar- In caterpillars of the moth H. zea, one salivary component, the vae, which is critical in modulation of plant development. This enzyme glucose oxidase (GOX), has been shown to suppress the lipase-like gene was hypothesized to either be directly involved production of nicotine, an inducible defensive compound produced in the establishment of larval feeding sites and cytological changes by tobacco host-plants (Musser et al., 2002). This enzyme has since observed in plant tissues during larval feeding, or to catalyze the been identified in the caterpillars of other Lepidoptera and in formation of a second messenger involved in signal transduction phloem-feeding insects such as aphids, suggesting suppression of leading to reprogramming of host cell tissues (Shukle et al., plant defenses via the secretion of this enzyme might be a common 2009). However, the majority of the salivary gland transcripts strategy used by different herbivores (Carolan et al., 2011; encoded small proteins (named secreted salivary gland proteins, Eichenseer et al., 2010; Harmel et al., 2008; Hogenhout and Bos, SSGPs), which lack sequence similarity to known proteins (Chen 2011). In certain lepidopteran–plant interactions, GOX is proposed et al., 2004), and for which little functional annotation is possible. to act on defensive response suppression by eliciting a SA burst, Similar diversity of novel secreted proteins is seen during gall which then negatively impacts JA and ET signaling pathways that induction by cynipid wasps (Hearn and Stone , unpublished data). regulate many induced defenses targeted against chewing herbi- SSGP coding genes were classified into multigenic families on the vores (Diezel et al., 2009; Musser et al., 2005). GOX may also play basis of sequence similarities (Chen et al., 2008) and certain genes a direct role in the inhibition of plant oxidative enzymes (i.e. lipox- appeared to be under strong positive selection suggesting they igenases, peroxidases) implicated in defense against insects encode effectors interacting with the host-plant (Chen et al., (Eichenseer et al., 2010). Whether this enzyme is also present in 2010b). SSGPs undergoing similar molecular evolution were also secretions of galling or leaf-mining insects remains to be identified in the Asian rice gall midge Orseolia oryzae, further sup- determined. porting the possibility that some of these proteins are effectors (Chen et al., 2010b). 3.2.2. ATP-hydrolyzing enzymes The recent sequencing of the M. destructor genome has allowed Three ATP-hydrolyzing enzymes (apyrase, ATP synthase and identification of the full putative effector repertoire, the genomic ATPase 13A1) were detected in the salivary glands H. zea caterpil- organization and remarkable expansion of the SSGP-encoding gene lars, and the purified recombinant proteins were shown to be able repertoire (Zhao et al., 2015). Interestingly, the largest gene family to suppress defensive genes regulated by JA and ET pathways in to be identified is composed of 426 SSGP-71 family members that tomato plants (Wu et al., 2012). These hydrolyzing enzymes pre- code for secreted proteins containing a cyclin-like F box domain in sumably act by degrading extracellular ATP (eATP) released by the N-terminus and a series of leucine-rich repeats (LRRs). In the plant during wounding and insect feeding (Guiguet et al., plants, F-box-LRR proteins interact with Skp1-like proteins that 2016). Indeed, when touched or wounded, plant cells release eATP are involved in targeting proteins for degradation in the protea- which acts as an early signaling molecule leading to increased con- some, and they play essential roles in hormonal signaling, plant centration in intracellular calcium, production of nitric oxide and development and plant defense. Zhao et al. (2015) propose that reactive oxygen species (ROS) and phosphorylation of mitogen- SSGP-71 proteins act as F-box-LRR mimics, in the same way as sim- activated protein kinases, ultimately leading to changes in gene ilar proteins described in bacterial plant pathogens (Angot et al., expression (Cao et al., 2014; Choi et al., 2014; Clark et al., 2014; 2006; Hicks and Galan, 2010), thereby hijacking the plant protea- Guiguet et al., 2016). In plants, eATP signaling impacts diverse pro- some leading to modified plant physiology. In accordance with this cesses including growth, development and responses to stress and hypothesis, a direct protein–protein interaction was observed pathogens (Cao et al., 2014; Clark et al., 2014). Levels of eATP are between an SSGP-71 protein and wheat Skp6 protein (Zhao et al., controlled by endogenous plant ATP-hydrolyzing enzymes, in par- 2015). ticular apyrases (Clark et al., 2014). Therefore, insect-derived apyr- In depth functional approaches are now required to determine ase enzymes constitute excellent candidate effectors to manipulate the role played by these proteins in the gall forming process, the these different aspects of plant physiology (Guiguet et al., 2016). In fact that RNA interference (RNAi) has been successfully applied accordance, since their characterization in H. zea, ATP-hydrolyzing to this galling insect model opens the path to unravel effectors enzymes have also been identified in oral secretions of other insect involved in gall formation in this species (Aggarwal et al., 2014). herbivores including Hessian fly (Chen et al., 2008; Hattori et al., More generally, with the progress made in RNA-seq and proteomic 2015). It will be of great interest to investigate whether these approaches, it is likely that more insect putative gall-inducing enzymes are secreted by other galling or leaf-mining insects given effectors will be characterized in other gall-inducing and their potential wide range of action on plant growth and immune D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 81 responses (Guiguet et al., 2016). It is noteworthy that these effec- of action of these different effectors are unknown, and whether tors are also used by insect parasites in their interaction with ani- they are involved in suppression of plant defense or in modifica- mal hosts (see Guiguet et al., 2016). tion of the nutritional environment is open to speculation. One M. persicae Mp10 protein has been shown to suppress the oxidative 3.2.3. Calcium-binding proteins burst response induced by a bacterial elicitor. However, in planta, Calcium-binding proteins have been identified in the salivary Mp10 expression causes a decrease in aphid fecundity, suggesting secretions of several insect herbivores including the Hessian fly that Mp10 plays the role of an avirulence-like effector in the (Afshar et al., 2013; Carolan et al., 2009; Chen et al., 2008; insect–plant interaction (Bos et al., 2010). More recently, a macro- Elzinga and Jander, 2013; Hattori et al., 2012; Nicholson et al., phage migration inhibitory factor (MIF) protein has been shown to 2012). In most cases, the mode of action of these proteins is be secreted in aphid saliva and play a crucial role for aphid sur- unknown, but one hypothesis is that they could suppress plant vival, fecundity and feeding on the host-plant. The ectopic expres- defense by interfering with early Ca2+ signaling triggered by insect sion of aphid MIF in leaf tissues inhibits major plant immune feeding (Guiguet et al., 2016). In the root-knot nematode, a calreti- responses including the expression of defense-related genes, cal- culin plays a role in the suppression of basal plant defenses (Favery lose deposition and hypersensitive cell death (Naessens et al., et al., 2016; Jaouannet et al., 2012). In the case of phloem-feeding 2015). Here again, MIF proteins are also used by parasites in their insects, calcium-binding proteins may play a role in limiting interactions with vertebrates – including nematodes, ticks and pro- phloem sieve-tube occlusion, which is triggered by calcium. In tozoa – suggesting common strategies among parasites of animal the vetch aphid, for example, calcium-binding proteins have been and plant species to disrupt the host immune response (Naessens proposed to interfere with specific legume proteins (forisomes) et al., 2015). that normally occlude sieve elements in response to calcium- triggered stress (Will et al., 2007; but see Knoblauch et al., 2014 3.3. Insect effectors and plant growth regulators for a counter-view). This molecular interaction between salivary proteins and calcium presumably provides these phloem-feeding Long standing candidate insect effectors include molecules that insects with a continuous flow of phloem-sap and may constitute are likely to regulate plant growth, defense and/or nutritional status one key mechanism at the basis of their successful colonization and many organisms are now known to be able to produce phyto- of plants. Calcium-binding proteins are also used by insect para- hormones. This includes gall-inducing bacteria (e.g. Stes et al., sites in their interactions with animal hosts suggesting calcium is 2011, 2013), nodulating bacteria (e.g. Frugier et al., 2008), plant- a central target for the disruption of cellular functions and a possi- associated fungi and viruses (e.g. Walters et al., 2008; Baliji et al., ble route of plant manipulation (see Guiguet et al., 2016). 2010), plant-parasitic nematodes (e.g. Favery et al., 2016; Siddique et al., 2015) and molluscan herbivores (Kästner et al., 2014). High 3.2.4. Other candidates levels of phytohormones have also been detected in the body, saliva Transcriptomic and proteomic analyses of aphid salivary glands or accessory glands of galling insects suggesting their ability to pro- or aphid saliva, combined in some cases with functional genomic duce and deliver these effectors to the plant (Bartlett and Connor, approaches, have revealed the presence of other potential effector 2014; Giron et al., 2013; Tooker and Helms, 2014). Several studies proteins (Elzinga and Jander, 2013; Hogenhout and Bos, 2011). have identified active auxin (IAA) in gall-inducing insects (Dorchin Some effectors have predictable functions, such as phenoloxidase et al., 2009; Mapes and Davies, 2001a; Tanaka et al., 2013; Tooker and peroxidase involved in detoxification of phenols and glucose and De Moraes, 2011a, 2011b; Yamaguchi et al., 2012) and in secre- dehydrogenase that could interfere with JA-regulated defense tions and frass produced by the European corn borer Ostrinia nubi- responses (Elzinga and Jander, 2013; Will et al., 2013). Functional lalis (Dafoe et al., 2013). ABA and CKs have also been found in studies involving gain-of-function (i.e. in planta overexpression of several galling insect species (Ohkawa, 1974; Dorchin et al., 2009; effectors) and/or loss-of-function (i.e. RNAi of effector expression) Giron et al., 2013; Mapes and Davies, 2001b; Straka et al., 2010; experiments have been successfully carried out for a small number Tanaka et al., 2013; Tooker and De Moraes, 2011a, 2011b; of aphid effectors. It will certainly be possible to develop similar Yamaguchi et al., 2012). CKs have also been found in the labial bioinformatics and functional pipelines (i.e. see Bos et al., 2010) glands of several leaf-miners including the birch green miner in order to characterize effectors produced by galling or leaf- (Engelbrecht, 1971; Engelbrecht et al., 1969) and the apple-tree mining insects. Overexpression of the Myzus persicae C002 effector leaf-miner (Body et al., 2013; Engelbrecht et al., 1969). in tobacco or Arabidopsis led to an increase in aphid reproduction Collectively these studies suggest that insects could be the (Bos et al., 2010; Pitino and Hogenhout, 2013), while reducing sources of these hormones – rather than simply manipulating the C002 gene expression by RNA silencing led to modified feeding plant phytohormonal balance/signaling – allowing them to hijack behavior and lethality in Acyrthosiphon pisum (Mutti et al., 2006, plant machinery for their own benefit. However, in most studies, 2008) and reduced fecundity in Myzus persicae (Pitino et al., it is not clear whether these molecules are synthesized de novo 2011). Molecular evolutionary analyses have revealed that this in the insect, or derived from ingested and sequestered plant tis- aphid-specific C002 gene is fast-evolving, suggesting that it may sue. Recently, an IAA biosynthetic pathway was identified in the play an adaptive role in aphids and could be involved in a co- silk worm Bombyx mori and a gall-inducing sawfly, suggesting that evolutionary arms race with host-plants (Ollivier et al., 2010; insects have the capacity to synthesize IAA in general (Suzuki et al., Pitino and Hogenhout, 2013). Other effectors with a beneficial 2014). Moreover, two gall-inducing insects, a sawfly and the Japa- effect on aphid reproduction and colonization have been identified, nese mugwort gall-midge Rhopalomyia yomogicola, have recently such as the M. persicae ‘‘Progeny Increase to Overexpression” pro- been shown to synthesize IAA de novo from tryptophan and are teins, PIntO1 and PIntO2 (Pitino and Hogenhout, 2013) and the also suspected of synthesizing CKs (Tanaka et al., 2013; Macrosiphon euphorbiae Me23 effector, that which increases this Yamaguchi et al., 2012). In vitro experiments and silencing of CK- aphid’s fecundity specifically on tobacco plants but not on tomato synthesizing genes (or other key regulatory genes involved in phy- (Atamian et al., 2013). Although it is still probably too early to gen- tohormone synthesis) as well as the use of plant mutants should eralize, the aphid effectors characterized to date seem to show help to determine the ability of insects to produce and deliver phy- specificity toward the aphid species (Pitino and Hogenhout, tohormones and the role played by these effectors in plant manip- 2013) and/or host-plant (Atamian et al., 2013), suggesting some ulation – as recently demonstrated for plant-parasitic nematodes effectors are involved in defining host range. However, the modes (Siddique et al., 2015). 82 D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89

3.4. Microbial partners and plant manipulation in insect–plant that P. syringae acts by suppressing anti-herbivore defenses medi- interactions ated by reactive oxygen species (Groen et al., 2016). It is also pos- sible that symbionts may be involved in the observed down- In the challenge to determine the exact origin of effectors regulation of plant defenses in the leaf-miner P. blancardella. involved in plant manipulation by insects, we should keep in mind Plant-associated symbionts (bacteria and viruses) may also play that microbial partners associated with insects may be involved. a role. They are involved in shaping the behavior of insect vectors Many invertebrates have intimate relationships with bacterial and could therefore potentially affect the impact of insect herbi- symbionts and it is also well known that genes involved in AUX vores on plants (Casteel and Hansen, 2014; Casteel and Jander, and CK synthesis can be of bacterial origin (Giron and Glevarec, 2013; Casteel et al., 2012; Mauck et al., 2010; Stafford et al., 2014). Microbial partners associated with insects, or even with 2011). Several plant pathogens are vectored by insects and can plants, can be key actors in insect–plant interactions (Douglas, modify plant defenses (Casteel and Hansen, 2014; Casteel et al., 2013; Frago et al., 2012; Sugio et al., 2015). Many phytophagous 2012). For example, the tomato spotted wilt virus vectored by insects are associated with microbial symbionts that provide the western flower thrips decreased JA-dependent defenses, via essential nutrients or defense against parasites (Bennett and the activation of the SA-signaling pathway, to the benefit of the Moran, 2015; Gibson and Hunter, 2010; Oliver et al., 2010). There insect (Abe et al., 2012). Similarly, the secretion by phy- is also growing evidence that insect-associated microbes are active topathogenic phytoplasma of the SAP11 protein led to down regu- players in plant manipulation to the benefit of the insect host lation of lipoxygenase gene expression and of JA synthesis, thereby (Body et al., 2013; Kaiser et al., 2010; Su et al., 2015; Sugio et al., increasing the survival and fecundity of the leafhopper vector 2015). Ongoing developments in genomic and transcriptomic tech- (Sugio et al., 2011). nology mean that it is increasingly possible to identify the source genomes of expressed genes. We can also explore which non- 3.4.2. Insect microbial symbionts and impact on plant nutritional plant gene products are present at which stage in gall induction, status and morphology and so identify candidate genes for more targeted expression The first survey of bacteria associated with the gut of a galling analyses. insect, the Hessian fly, has recently revealed a predominance of Pseudomonas species (Bansal et al., 2014), the genomes of which 3.4.1. Insect symbionts and suppression of plant defense were identified in whole genome sequencing of M. destructor Several groups have reported the involvement of insect sym- (Zhao et al., 2015). It remains to be seen whether these bacteria bionts in the suppression of plant defenses. A very elegant study or other microbes associated with the insect modify host-plant showed the Colorado potato beetle (Leptinotarsa decemlineata)to nutrition and development, leading to gall induction. Some gall release bacteria in its oral secretions, resulting in the activation midges have a symbiotic association with biotrophic fungi that of a plant microbial defense response. This induction of the are essential for invasion of plant stems and access to vascular tis- SA-signaling pathway led, in turn, by negative cross-talk, to down- sue, for providing larvae with highly nutritious food and for gall regulation of the JA-responsive anti-herbivore response. The development (Rohfritsch, 2008). The molecular mechanisms beetles benefited from this manipulation by improved larval underlying such tripartite interactions involving fungi will also growth (Chung et al., 2013). These results show that the herbivore be very interesting to uncover. Curing the apple-tree leaf-miner literally exploits symbiotic bacteria, using them as effectors P. blancardella of its endosymbiotic Wolbachia bacteria resulted in and a ‘smoke screen’, to disrupt plant perception and evade the loss of the CK-induced green-island phenotype on apple-tree anti-herbivore defenses. Plant defense suppression involving leaves, and in the absence of detectable CKs in larvae compared insect-associated bacteria was also suggested in the maize–corn to non-treated controls (Body et al., 2013; Kaiser et al., 2010). rootworm interaction, in which Wolbachia infection was positively These results suggest that these insects have the ability to modify correlated with ability of the moth larvae to inhibit defense gene the phytohormonal profile in mined leaf tissues and to deliver CKs expression in the maize (Barr et al., 2010). However, further work to the plant via their association with symbiotic bacteria (Zhang showed that endosymbiont-free insects do not elicit different et al., 2016). So far, no other studies have linked insect symbionts maize defense responses to Wolbachia-infected insects (Robert to the plant metabolic status, but it will be of great interest to et al., 2013) suggesting that symbiont effects can be context- determine whether similar mechanisms are used in other plant– dependent. In the whitefly Bemisia tabaci, saliva of whiteflies insect interactions. harboring the facultative symbiont Hamiltonella defensa is able to Cornell (1983) suggested that viruses or viral proteins could be suppressed JA-related defenses in tomato compared to saliva from involved in the delivery of gall-inducing stimuli in cynipids. A non-infected controls (Su et al., 2015). Putative non proteinaceous model for this hypothesis is shown in some endoparasitoid wasps, effectors were identified in the saliva, and it will be now very inter- which have incorporated polydnavirus viral coat protein genes into esting to determine their origin and exactly how H. defensa medi- their own genomes, producing virus-like particles with which they ates the suppression of plant defenses in this system. Hamiltonella deliver other gene products to their lepidopteran hosts, resulting in may serve as a nutrient provider in whiteflies (Luan et al., 2015), immune system suppression (Bézier et al., 2009; Quicke, 2015). illustrating the multiple ways in which a symbiont can impact However, no evidence for this theory yet exists in gall-inducing overall insect fitness. Taken together, work to date shows that wasps. insect-associated microorganisms can influence plant defense reactions. The role of these partners in different plant–insect inter- 3.4.3. Insect microbial symbionts and effectors encoded by horizontally actions may therefore have to be evaluated in more detail. For transferred genes example, feeding by the silverleaf whitefly has been shown to Recent studies have shown that microbial effectors impacting induce SA defenses and to suppress JA responses (Zarate et al., insect–plant interactions can be encoded by genes incorporated 2007). It remains to be seen whether this ability is endogenous into insect genomes following horizontal gene transfer (HGT) from to the insect or is symbiont-associated. Very interestingly, it was bacteria (Boto, 2014). HGT has long been recognized as an impor- recently shown in an interaction involving Scaptomyza flava leaf- tant process governing the evolution of prokaryote genomes, and miner, that the larvae can vector Pseudomonas syringae bacteria increasing genome sequencing shows the same process to be to and from feeding sites and that the larvae perform better on widespread in the evolution of eukaryote genomes, leading to plants infected with P. syringae. Here the suggested mechanism is the acquisition of novel traits (Syvanen, 2012). HGT in arthropods D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 83 appears to be particularly widespread, probably because of the aspects of insect nutritional ecology, it seems highly likely that close association of many insects with endosymbionts, although symbionts will be part of the story, some of the time (Gibson and the adaptive significance of these horizontally transferred genes Hunter, 2010). is not always evident (Hotopp et al., 2007; Kondo et al., 2002; Nikoh et al., 2008; Werren et al., 2010). In some cases, HGT are pro- 4. Concluding thoughts posed to facilitate genome reduction of endosymbionts, sometimes leading to complex nested symbioses within phytophagous insects Galls are commonly distinguished from other insect-generated (Husnik et al., 2013; Sloan et al., 2014). shelters such as rolled leaves and leaf mines by the fact that they Two of the most convincing examples of HGT concern genes involve active differentiation and growth of plant tissues (Crespi derived from non-endosymbiotic bacteria, most probably involved et al., 1997; Shorthouse and Rohfritsch, 1992; Stone and in the adaptation of insects to a herbivorous lifestyle. Horizontally Schönrogge, 2003; Williams, 1994). It is generally assumed that transferred genes coding enzymes involved in degradation of leaf-miners do not manipulate their host-plant, but constitute an polysaccharides in plant cell-walls have been identified in two intermediate evolutionary step toward more sophisticated plant phytophagous beetles (Acuña et al., 2012; Pauchet and Heckel, manipulation strategies (Fig. 2)(Price et al., 1987). However, the 2013). The genome of the coffee berry borer beetle includes an oldest leaf-miner fossil records date to the Triassic period of the expressed and functional mannanase gene that is phylogenetically Mesozoic era, 248–206 million years ago (mya) (Labandeira, related to Bacillus genes, and is presumed to facilitate the beetle’s 2002; Labandeira et al., 1994; Rozefelds, 1988; Rozefelds and feeding within the coffee berry (Acuña et al., 2012). Similarly, the Sobbe, 1987), postdating the oldest gall-inducing lineages genome of the mustard leaf beetle has acquired two functional (300 mya). Rather than seeing leaf-miners as antecedents to xylanases, probably through tandem gene duplication, after HGT sophisticated plant manipulators, this review presents several lines of a gamma-proteobacteria xylanase gene (Pauchet and Heckel, of evidence that leaf-miners are true plant reprogrammers, in some 2013). Interestingly, HGT of genes encoding plant cell-wall degrad- ways paralleling gall-inducers in their ability to modify source-sink ing enzymes have also been identified in cynipid wasps (Hearn and relationships, plant morphology, nutrient availability and defenses Stone, unpublished data) and in plant parasitic nematodes (Abad to the insect’s advantage (Table 1). The extent to which similarities et al., 2008; Danchin and Rosso, 2012; Danchin et al., 2010; between leaf-miners and gallers reflect shared ancestral traits or Favery et al., 2016; Opperman et al., 2008), suggesting acquisition convergent evolution remains to be explored. of genes by HGT in general may play an important role in Feeding strategies used by plant reprogrammers presumably transitions to plant parasitic lifestyles, or to herbivory on specific evolved to face similar constraints partially imposed by the endo- host-plants or tissues. Thirty candidate HGT events were recently phytic lifestyle shared by leaf-miners and most gall-inducers identified in the Hessian fly, again with most encoding enzymes (Dempewolf et al., 2005; Stone and Schönrogge, 2003). Like insects involved in carbohydrate metabolism, suggesting they allow the in closed galls, leaf-miners simultaneously live in and eat their insect to better digest plant carbohydrates (Zhao et al., 2015). HGTs plants with no possibility to escape in case of inadequate food sup- involved in direct plant defense suppression, modification of plant ply (due to plant defensive mechanisms and/or seasonal variations metabolism or gall induction have so far not been identified, but of the plant quality) or attack by natural enemies (Sinclair and growing research into the genomics and transcriptomics of non- Hughes, 2010; Stone and Schönrogge, 2003). The main hypotheses model plant-herbivore interactions is increasing the chance that for the adaptive significance of gall-induction (nutrition, microcli- such interactions, if present, will be found. mate, defense) can also be applied to leaf-miners (Connor and Taverner, 1997; Sinclair and Hughes, 2010). Performance of gall- 3.4.4. Microbes and insect plant specialization inducers and leaf-miners is also highly dependent on the oviposi- Symbiotic bacteria associated with insects could play a role in tion choice of their mother, a characteristics shared with all insects plant adaptation, specialization or expansion of host range that have relatively sessile developmental stages. (Henry et al., 2013; Medina et al., 2011; Oliver et al., 2010; Toju The ‘‘plant response approach” adopted here highlights key can- and Fukatsu, 2011; Tsuchida et al., 2011). Chu et al. (2013) recently didate plant functions that need to be disrupted for the insect to showed that the gut microbiome of the western corn rootworm establish itself and feed successfully. The development of new Diabrotica virgifera virgifera is an important actor in facilitating sequencing techniques applicable to small and/or non-model spe- adaptation to soybean herbivory. Interspecific transfer of cies will accelerate identification of insect effectors. A fascinating endosymbionts between stinkbug species has also been shown to possibility is that insects could manipulate plant development improve the recipeinet’s performance on soybean (Hosokawa through synthesis of plant small interfering RNAs incorporated et al., 2007). In Japan, host-plant specialization of pea aphid is into their genomes. As this field develops, access to sequences for affected by facultative endosymbiotic bacteria and experimental candidate effectors will allow comparative studies across insect transfer of the facultative symbiont Regiella insecticola in vetch radiations, and comparison with other lineages, such as plant- aphids allowed some adaptation to clover plants (Tsuchida et al., parasitic nematodes. Merging studies on altered patterns of plant 2011). However, to date the mechanisms by which these bacteria gene expression – and related plant metabolic and morphological allow adaptation to host-plants is unknown. They could involve responses – and salivary effectors produced by plant- direct impacts on the insect such as modifications of gut enzyme manipulating insects will undoubtedly help to identify targeted activities (Chu et al., 2013), but manipulation of plant defenses plant functions. This should contribute to identify strategies used or plant nutrients could also be involved. The pea aphid, A. pisum, by insects to manipulate their host-plant paving the way toward encompasses multiple plant-specialized biotypes, each adapted to the discovery of mechanisms underlying gall induction and one or a few legume species. Facultative symbiont communities growth. One of the most significant bottlenecks to this end is the differ strongly between biotypes and plant specialization is an identification and characterization of plant receptors that perceive important structuring factor of bacterial communities associated the herbivore-specific elicitors and effectors (Acevedo et al., 2015). with the pea aphid complex (Gauthier et al., 2015; Peccoud et al., More well-assembled genomes for plant-manipulators and their 2015). Here again, the role played by bacterial symbionts in plant hosts are now required, so that we can use the techniques of classi- specialization is uncertain. Whether galling or leaf-mining insects cal quantitative genetics and genomics (e.g. genome-wide associa- harbor symbiotic bacteria that could also be involved in plant tion studies, map-based cloning, or sliding window pairwise adaptation remains little unexplored. Given their roles in so many genome comparisons between pairs of divergent lineages inducing 84 D. Giron et al. / Journal of Insect Physiology 84 (2016) 70–89 contrasting gall phenotypes) to identify candidate genes involved in Afshar, K., Dube, F.F., Najafabadi, H.S., Bonneil, E., Thibault, P., Salavati, R., Bede, J.C., gall phenotypes or metabolism, and then link these to genomic 2013. Insights into the insect salivary gland proteome: diet-associated changes in caterpillar labial salivary proteins. J. Insect Physiol. 59, 351–366. regions (e.g. Zhao et al., 2015, 2016). A full understanding of the Aggarwal, R., Subramanyam, S., Zhao, C., Chen, M.S., Harris, M.O., Stuart, J.J., 2014. transcriptomics and metabolomics of non-galled/non-mined tis- Avirulence effector discovery in a plant galling and plant parasitic arthropod, sues on the same plants is also needed before we can highlight the hessian fly (Mayetiola destructor). PLoS One 9, e100958. Allison, S.D., Schultz, J.C., 2005. Biochemical responses of chestnut oak to a galling the true impacts of plant reprogrammers (e.g. Body, 2013; Zhang cynipid. J. Chem. Ecol. 31, 151–166. et al., 2016). Cytological and histochemical analyses are still among Anderson, K.G., Harris, M.O., 2006. Does R gene resistance to hessian fly allow wheat the best ways to understand altered plant development (Harris seedlings to escape larval-induced growth deficits? J. Econ. Entomol. 99, 1842– 1853. et al., 2006, 2010; Oliveira et al., 2016) and in situ hybridization Anderson, K.G., Harris, M.O., 2008. Leaf growth signals the onset of effective plant (FISH) can be used for example to show spatial and temporal resistance against hessian fly larvae. Entomol. Exp. Appl. 128, 184–195. expression patterns of candidate genes targeted by plant repro- Angot, A., Peeters, N., Lechner, E., Vailleau, F., Baud, C., Gentzbittel, L., Sartorel, E., Genschik, P., Boucher, C., Genin, S., 2006. Ralstonia solanacearum requires F-box- grammers. Finally, model systems that have been studied in suffi- like domain-containing type III effectors to promote disease on several host cient detail (e.g. Body, 2013; Harris et al., 2003; Giron et al., 2013; plants. Proc. Natl. Acad. Sci. USA 103, 14620–14625. Stone and Schönrogge, 2003) and for which molecular resources Arnold, T.M., Appel, H.M., Schultz, J.C., 2012. Is polyphenol induction simply a result are available (e.g. Giron and Huguet, 2011; Whiteman et al., of altered carbon and nitrogen accumulation? Plant Signal. Behav. 7, 1498– 1500. 2011; Zhao et al., 2015) could be used to develop RNA interference Atamian, H.S., Chaudhary, R., Dal Cin, V., Bao, E., Girke, T., Kaloshian, I., 2013. In approaches to knock out candidate gene expression, and so better planta expression or delivery of potato aphid Macrosiphum euphorbiae effectors understand the impacts of specific inducers and plant genes. As col- me10 and Me23 enhances aphid fecundity. Mol. Plant Microbe Interact. 26, 67– 74. leagues in plant pathology have already experienced (Schneider Atkinson, R.J., McVean, G.A.T., Stone, G.N., 2002. Use of population genetic data to and Collmer, 2010), developing gain- and loss-of-function infer oviposition behaviour: species-specific patterns in four oak gallwasps approaches is challenging but is now required to understand the (Hymenoptera: Cynipidae). Proc. R. Soc. Ser. B 269, 383–390. Atkinson, R.J., Brown, G.S., Stone, G.N., 2003. Skewed sex ratios and multiple proximal mechanisms at the basis of insect-induced plant manipu- founding in galls of the oak apple gallwasp Biorhiza pallida. Ecol. Entomol. 28, lations both in leaf-mining and gall-inducing species. 14–24. Bagatto, G., Paquette, L.C., Shorthouse, J.D., 1996. Influence of galls of Phanacis taraxaci on carbon partitioning within common dandelion, Taraxacum officinale. Acknowledgements Entomol. Exp. Appl. 79, 111–117. Bailey, R., Schönrogge, K., Cook, J.M., Melika, G., Csóka, Gy., Thúroczy, Cs., Stone, G. N., 2009. Host niches and defensive extended phenotypes structure parasitoid This study has been supported by the ANR – France Grant No. wasp communities. PLoS Biol. 7, e1000179. ANR-05-JCJC-0203-01 and the Région Centre Projects – France Baliji, S., Lacatus, G., Sunter, G., 2010. The interaction between geminivirus 2010-00047141 and 2014-00094521 to D. Giron. Further support pathogenicity proteins and adenosine kinase leads to increased expression of primary cytokinin-responsive genes. Virology 402, 238–247. was provided by the National Centre of Scientific Research (CNRS) Bansal, R., Hulbert, S.H., Reese, J.C., Whitworth, R.J., Stuart, J.J., Chen, M.S., 2014. – France and the University François-Rabelais de Tours – France. Pyrosequencing reveals the predominance of Pseudomonadaceae in gut Graham Stone’s work was supported by UK NERC Grant NE/ microbiome of a gall midge. Pathogens 3, 459–472. 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