Pharmacological approaches to nitric oxide signalling during neural development of locusts and other model insects.код для вставкиСкачать
Archives of Insect Biochemistry and Physiology 64:43� (2007) Pharmacological Approaches to Nitric Oxide Signalling During Neural Development of Locusts and Other Model Insects Gerd Bicker* A novel aspect of cellular signalling during the formation of the nervous system is the involvement of the messenger molecule nitric oxide (NO), which has been discovered in the mammalian vascular system as mediator of smooth muscle relaxation. NO is a membrane-permeant molecule, which activates soluble guanylyl cyclase (sGC) and leads to the formation of cyclic GMP (cGMP) in target cells. The analysis of specific cell types in model insects such as Locusta, Schistocerca, Acheta, Manduca, and Drosophila shows that the NO/cGMP pathway is required for the stabilization of photoreceptor growth cones at the start of synaptic assembly in the optic lobe, for regulation of cell proliferation, and for correct outgrowth of pioneer neurons. Inhibition of the NOS and sGC enzymes combined with rescue experiments show that NO, and potentially also another atypical messenger, carbon monoxide (CO), orchestrate cell migration of enteric neurons. Cultured insect embryos are accessible model systems in which the molecular pathways linking cytoskeletal rearrangement to directed cell movements can be analyzed in natural settings. Based on the results obtained from the insect models, I discuss current evidence for NO and cGMP as essential signalling molecules for the development of vertebrate brains. Arch. Insect Biochem. Physiol. 64:43�, 2007. � 2006 Wiley-Liss, Inc. KEYWORDS : cGMP; cell proliferation; cell migration; growth cone; pioneer neuron; pest insects INTRODUCTION biochemical and immunocytochemical evidence for NO signalling in the orthopteran nervous system, Nitric oxide (NO) is an atypical cellular messen- focussing mainly on the physiological roles of NO ger that plays multiple functions in the vascular, im- in sensory and motor circuits. In this report, I ad- mune, and nervous system. In the vertebrate brain, dress essential functions of this membrane-permeant NO is a key signalling molecule that has been im- messenger during development of the nervous sys- plicated in cell proliferation, synaptogenesis, syn- tem. Embryonic locusts are especially useful mod- aptic plasticity, and neurological disease (Boehning els of developmental neurobiology because cell and Snyder, 2003; Godfrey and Schwarte, 2003; biological mechanisms of axon guidance can be Packer et al. 2003; Keynes and Garthwaite, 2004). studied at the level of single identified neurons For about a decade, two locust species (Locusta (Goodman and Bate, 1981; Bentley and O扖onnor, migratoria, Schistocerca gregaria) have been used as 1992; Boyan et al., 1995; Burrows, 1996; Legg and key experimental animals to unravel NO-mediated O扖onnor, 2003). In addition, this review will in- processes in the physiology and development of clude evidence for a functional role of NO in hemimetabolous insects. In a former review of this neurodevelopment from investigations of other well- field (Bicker, 2001), I have tried to summarize the studied holometabolous insect species. University of Veterinary Medicine Hannover, Cell Biology, Institute of Physiology, Hannover, Germany Contract grant sponsor: Deutsche Forschungsgemeinschaft. *Correspondence to: Gerd Bicker, University of Veterinary Medicine Hannover, Cell Biology, Institute of Physiology, Bischofsholer Damm 15, D-30173 Hannover, Germany. E-mail: email@example.com Received 30 May 2006; Accepted 12 October 2006. � 2006 Wiley-Liss, Inc. DOI: 10.1002/arch.20161 Published online in Wiley InterScience (www.interscience.wiley.com) 44 Bicker In nerve cells, NO is generated in an activity- 2+ stream effector proteins, including cGMP-depen- /calmodulin-stimulated dent protein kinases (PKG), phosphodiesterases, nitric oxide synthases (NOS) (Bredt and Snyder and cyclic nucleotide-gated ion channels (Lucas et 1992; Garthwaite and Boulton 1995). NOS cata- al., 2000). It is possible to identify cellular targets lyze the production of NO and L-citrulline from by the capacity of NO to stimulate cGMP synthe- L-arginine and O 2. Since this reaction requires sis (Fig. 1). After exposure of nervous tissue to nicotinamide adenine dinucleotide phosphate chemicals releasing NO, the accumulation of cGMP (NADPH) as a cofactor, NADPH-diaphorase his- can be visualized with specific antisera to cGMP tochemistry (NADPHd) following formaldehyde (DeVente et al., 1987). However, it should be em- fixation of neural tissue is a popular method for phasized that the NOS and sGC enzyme activities staining NOS-expressing cells (Matsumoto et al., may also be under the control of other regulatory 1993). In various regions of the adult locust ner- ligands (Boehning and Snyder, 2003). Moreover, vous system, measurements of NOS activity in cell even though stimulation of sGC is a major trans- homogenates of various regions correlate quite well duction pathway of the NO signalling cascade, with the biochemical determination of NADPHd other transduction pathways that signal through activity and the histochemical staining pattern of redox events are possible (Stamler et al., 1997). NADPHd-positive cells (M黮ler and Bicker; 1994; Using NO-releasing compounds to induce cGMP Elphick et al., 1995). Nevertheless, in some insects synthesis in the locust brain, both a separate and the results of the diaphorase staining are rather sen- a co-localized cellular distribution of NADPHd ex- sitive to variations in the histochemical protocol pression and cGMP-immunoreactivity (cGMP-IR) and some fixation conditions are even thought to can be found (Bicker et al., 1996, 1997; Bicker and cause dependent process by Ca Burrows, Schmachtenberg, 1997; Ott et al., 2004). These 1999). Using an antiserum that recognizes a highly anatomical studies suggest that in some regions of conserved sequence of different mammalian NOS the nervous system, NO may not only act as a isoforms, it has been shown for the locust that paracrine but also as an autocrine signal. false-positive results (Ott and NOS-immunoreactivity (NOS-IR) does indeed co- A further complex issue in the regulation of cel- localize with NADPHd-positive cell bodies on lular cGMP levels in invertebrates is the biosynthetic double-stained cryosections of the antennal lobe activity of other enzymes, such as the so-called (Bicker, ganglia 揳typical� soluble guanylyl cyclases that are mainly (Bullerjahn and Pfl黦er, 2003). These findings insensitive to NO and most likely function as mo- would support the molecular identity of diapho- lecular oxygen sensors and additional receptor rase and NOS enzymes, at least for the central ner- guanylyl cyclases, integral membrane proteins that vous system. are stimulated by peptide ligands (Morton, 2004). 2001) and in the abdominal The product of NOS activity, NO is thought to In contrast to the presence of several NOS genes diffuse as a short-lived transcellular messenger from in mammalian tissue (Bredt and Snyder 1992; its site of production across cell membranes. Since Garthwaite and Boulton 1995), only a single gene NO is converted to nitrites and nitrates by react- locus has been found in ing with oxygen in water, it has a half life of about Tully, 1995; Enikolopov et al., 1999). This locus 5� sec. NO acts mainly via stimulation of the codes for an extended family of transcripts that may heme sensor protein soluble guanylyl cyclase (sGC; produce several NOS-related proteins (Enikopolov Bellamy and Garthwaite, 2002). By selective bind- et al., 1999). A genetic study suggests that NO has ing at the heme iron of this enzyme, NO triggers a an important function for the developing organ- conformational shift, activating sGC to convert gua- ism. Flies that are homozygous for a point muta- nosine triphosphate (GTP) to cyclic guanosine tion in the NOS gene die during late embryonic monophosphate (cGMP), an intracellular second and early larval stages for reasons that are not yet messenger. cGMP can then activate various down- known (Regulski et al., 2004). Thus, there is a need Drosophila Archives of Insect Biochemistry and Physiology (Regulski and January 2007 doi: 10.1002/arch. Nitric Oxide Signaling During Insect Development 45 tric oxide application by producing cGMP (Truman et al., 1996). Sometimes cGMP-IR is not only found in the cytosol but also in the nucleus, suggesting that cGMP may be involved in transcriptional regulation. Nuclear localization of cGMP-IR is typical of neurons that are early in their maturational phase and is absent in cells once their synaptic contacts have been established. Some of the NO-responsive cells are identified motoneurons showing cGMP-IR axonal growth cones. The sensitivity to NO appears after the growth cone has arrived at its target but before branches have started to explore the muscle, reflecting the transition from longitudinal elongation to the formation of lateral Pharmacological manipulation of transcellular branch growth. This led to the hypothesis (Ball and NO/cGMP signal transduction. An increase in intracellu- Truman, 1998) that cGMP plays a role in the early lar Ca of the donor cell stimulates the nitric oxide syn- stages of communication between a postsynaptic thase (NOS) enzyme. NOS activity can be blocked by bath target and specific innervating neurons. Moreover, application of the inhibitor 7-nitroindazole (7Ni). NO certain sensory and interneurons also become NO diffuses from the donor cell to a target cell, binds to the receptive as they change from axonal outgrowth Fig. 1 2+ heme moiety in soluble guanylyl cyclase (sGC) resulting in the stimulation of the enzyme and consequent elevation of cGMP concentration. sGC activity is blocked by the inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1one (ODQ) and stimulated independently from NO by the sGC activator protoporphyrin IX free acid (Protoporphyrin IX). Synthesis of cGMP may activate protein kinase G (PKG) and regulate downstream cellular responses. to synaptogenesis (Truman et al., 1996; Ball and Truman, 1998). In contrast to a transient NO sensitivity during development, a set of subepidermal plexus neurons of Manduca express a persistent NO- induced cGMP-IR throughout larval life (Grueber and Truman, 1999). NO-induced cGMP formation has also been described in differentiating sensory The PKG inhibitor 8-Bromo-guanosine 3�,5�-cyclic mono- cells of the imaginal leg discs and during synaptic phosphorothioate Rp-Isomer (RpcGMPS) blocks cellular maturation at the larval neuromuscular junction responses of the cGMP/PKG pathway. The NO donor so- of Drosophila (Wildemann and Bicker, 1999a,b). dium nitroprusside (SNP) and the membrane-permeable NO and cGMP appear to regulate not only neu- cGMP analogon 8-Bromo-cGMP (8Br-cGMP) can be ap- romuscular connectivity but also the formation of plied to raise cGMP levels in the target cell. the retinal projection pattern of the visual system. During visual system formation in Drosophila pu- for complementary approaches to unravel the po- pae, the photoreceptors respond to NO stimula- tentially very important roles that NO may play tion with the synthesis of cGMP during a specific during the formation of insect nervous systems. temporal window, while the postsynaptic optic ganglia stain for NADPH-diaphorase (Gibbs and NO/cGMP SIGNALING DURING FORMATION OF Truman, 1998). Pharmacological interference with NEURAL CONNECTIVITY NO/cGMP signal transduction disrupts the establishment of proper retinal connections into the One of the earliest ideas about the potential optic lobe, such that photoreceptor axons extend roles of NO/cGMP signaling came from expression beyond their normal synaptic targets. There is ad- studies of NO-induced cGMP-IR in embryonic ditional genetic evidence for the involvement of grasshoppers. During synaptogenesis, many iden- sGC in retinal patterning of tifiable nerve cell types respond to exogenous ni- morphic mutant in the Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. Drosophila a-subunit . A hypo- gene of sGC 46 Bicker shows minor defects in the retinal projection pat- that traverse the route from their origin near the tip tern. Pharmacological NOS inhibition on top of of each appendage to the CNS, when distances are the genetic defect increased visual system disorga- short (Bate, 1976; Bentley and O扖onnor, 1992). nization in mutants to a greater degree than in the Pathfinding seems to involve selective adhesion of wild type (Gibbs et al., 2001). the growth cones to substrate bound guidance cues In the tobacco hornworm Manduca sexta, an and partly by recognition of guide post cells upregulation of cGMP levels parallels the phase (Bentley and O扖onnor, 1992). In the thoracic of synaptogenesis in the pupal antennal lobe limb bud, two gradients of the semaphorin cell rec- (Schachtner et al., 1998). Nearly all local interneu- ognition molecule Sema-2a have been identified rons express that are necessary for the directional guidance of cGMP-IR in response to the steroid hormone 20- the pioneer growth cones from the periphery to- hydroxyecdysone. However, only in a subpopula- wards the CNS (Isbister et al., 1999; Legg and tion of these interneurons are cGMP elevations O扖onnor, 2003). of the developing antennal lobe controlled directly by NO, possibly released by Similar to the limb buds, the first neural path- the many NADPHd-stained neurons of the lobe ways in the antenna of the grasshopper are also (Schachtner et al., 1999). Pharmacological inter- established by two identified pairs of pioneer neu- ference with the NO/cGMP signaling pathway re- rons at the tip of the antennal anlage. The ventral sults in reduction of the ubiquitous synaptic vesicle and dorsal pioneers send their neurites in separate protein synaptotagmin, suggesting that NO en- pathways proximally, targeting a guide post cell at hances the rate of synaptogenesis during develop- the base of the antennal anlage (Bate, 1976; Ho ment of olfactory glomeruli via cGMP (Schachtner, and Goodman, 1982, Berlot and Goodman 1984). 2005). In summary, the appearance of a stage-de- According to Ho and Goodman (1982) the axon pendent NO-induced cGMP-synthesis in selective of this base pioneer is the first peripheral process neuronal cell types appears to be a rather com- to reach the CNS from the antenna. It was origi- mon developmental phenomenon both in hemi- nally thought that the axons of the pioneers at the and holometabolous insects, ranging from the tip of the anlage prefigure two axonal fascicles to primitive silverfish to highly developed lepidopter- the brain, which are joined by later born sensory ans and dipterans (Truman et al., 1996; Schachtner neurons on the annular segments to form the bi- et al., 1998; Wright et al., 1998; Wildemann and partite antennal nerve of larval and adult stages. Bicker, 1999a). Even though all these investigations However, a recent re-investigation by Boyan and Wil- have provided evidence for a role of NO/cGMP sig- liams (2004) has suggested that the ventral and dor- nalling during the assembly of neuronal connec- sal tract of the antenna is not pioneered alone from tivity, its precise cellular mechanisms are still a the tip of the antenna, but in a stepwise manner by mystery. sets of pioneers arising in additional annular segments. Moreover, some of these more proximally PIONEERING NO/cGMP SIGNALLING located pioneers may correspond to the so-called base pioneer mentioned in the literature to be po- Pioneer neurons establish the first axonal path- sitioned at various locations on the antenna (Ho ways that are followed by later-growing axons using and Goodman, 1982; Berlot and Goodman, 1984; mechanisms of contact guidance. This pathfinding Seidel and Bicker, 2000). strategy is beautifully exemplified in grasshopper Developmental neurobiologists are accustomed embryos where the early axonal pathways in the to the concept of neurite outgrowth as being peripheral nervous system are laid down by easily guided by the extracellular distribution of attrac- identifiable pioneer neurons. For example, the neu- tive and repellent guidance cues. These guidance ral pathways in the antenna and limb are estab- cues comprise secreted or cell surface朾ound fami- lished by specific pairs of peripheral pioneer neurons lies of proteins that are ligands of specific receptor Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. Nitric Oxide Signaling During Insect Development 47 types on the membrane of motile growth cones over, it will be interesting to know whether other (Song and Poo, 2001; Dickson, 2002; Chilton, neurons showing NO-induced cGMP-IR are also 2006). Within this conceptual framework, immu- dependent on NO/cGMP for neurite outgrowth. nocytochemical evidence for a role of the gaseous Our recent investigations of the grasshopper em- messenger NO in growth cone behavior of pioneer bryo indicate that NO/cGMP is not only critical neurons was somewhat surprising. Outgrowing for growth cone extension of the antennal pioneers, pioneer neurons at the tip of the antenna synthe- but also for outgrowth of the other peripheral pio- size cGMP in response to exogenous NO treatment neers of the limbs (P鋞schke and Bicker, 2006). (Seidel and Bicker, 2000). To search for potential In molluscan neurons expressing NOS, there is cellular sources of NO, NADPHd histochemistry also comparable experimental evidence for an in- was used. Parts of the epithelial cells that face the trinsic regulation of neurite outgrowth (Van Wagenen basal lamina in the embryonic antenna transiently and Rehder, 1999). NO orchestrates two aspects stain for NADPHd, suggesting transcellular NO/ of growth cone behavior in an identified neuron Helisoma cGMP signalling from the epithelium to the out- from the buccal ganglion of the snail growing pioneers. The staining of the basal parts namely neurite outgrowth and filopodial dynam- of epithelial cells during pioneer neuron outgrowth ics. This neuron contains both NOS and sGC en- is not very pronounced, but the staining intensity zymes, which can be localized to the growth cone, was much greater compared to the mesodermal tis- suggesting the capability of autostimulation by sue bordering the basal lamina. Diaphorase stain- NO/cGMP signalling. Pharmacological manipula- ing of the epithelial cells is visible during a period tions in cell culture demonstrate that the effects of ranging from about 32�% of embryonic devel- exogenous NO application on neurite outgrowth opment and disappears at later stages. are mediated via cGMP, PKG, cyclic ADP ribose, Using an embryo culture system, it can be and intracellular Ca 2+ , release (Van Wagenen and shown that pharmacological inhibition of endog- Rehder, 2001; Trimm and Rehder, 2004; Welshhans enous NO synthase and sGC activity results in a and Rehder, 2005). perturbation of the pioneering pathways from the The experimental analysis of neurite extension tip of the antenna. To link the phenotypical defect using individual snail and grasshopper neurons has of disruption in pioneer outgrowth to a molecular revealed that one of the developmental functions inhibition of NO/cGMP formation, unspecific side of NO/cGMP signalling serves the regulation of cel- effects of the pharmacological enzyme inhibitors lular motility. Thus, it is easy to imagine that en- have to be ruled out. Since the pharmacological dogenous NO production in developing nervous disruption of pioneering pathways can be rescued systems can influence the establishment of synap- by supplementing the whole embryo culture with tic contacts including dynamic structural changes membrane-permeant cGMP and with a NO-inde- during synapse maturation. Furthermore, knowl- pendent activator of sGC (Seidel and Bicker 2000), edge about neuronal growth regulation by NO unspecific side effects of the enzyme blockers are could be of practical importance in understanding unlikely. Thus, embryonic pioneer neuron out- general constraints of neural repair. Compared to growth constitutes an accessible in vivo system in wild-type, neuronal NOS knockout mice show a which the role of NO/cGMP signaling during path- delay in sciatic nerve regeneration and recovery of finding can be analyzed at the level of identified sensory-motor-function (Keilhoff et al., 2002). nerve cells. Remodeling of the cytoskeleton pro- These results suggest that release of NO following vides the driving force for neurite outgrowth in any peripheral nerve injury may play a beneficial role developing nervous system. Therefore, it will be of in mammalian nerve regeneration. There is mor- importance to unravel intracellular signaling path- phological evidence for axonal regeneration after ways that regulate the NO/cGMP-induced changes crushing a connective in the central nervous sys- in the cytoskeleton of the pioneer neurons. More- tem of the locust (P鋞schke et al., 2004). Intrigu- Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. 48 Bicker ingly, blocking the NOS pathway impairs axonal regeneration of identified central neurons during early development (Stern, 2006), emphasizing a role for NO as a positive regulator of axonal regeneration mechanisms in insects. NO WAYS FOR CELL MIGRATION IN THE ENTERIC NERVOUS SYSTEM Since molecular guidance cues of axonal outgrowth are also used for directed movements of neuronal cell bodies (Song and Poo, 2001), our laboratory (Haase and Bicker, 2003) and others (Wright et al., 1998) were wondering if NO/cGMP signalling might influence migration of embryonic insect neurons. The formation of the insect stomatogastric or enteric nervous system (ENS) provides a well-established model to study the cell biology of neuronal migration (Hartenstein, 1997). The midgut plexus (MG) neurons of the grasshopper embryo arise in a neurogenic zone in the foregut, forming a packet of postmitotic but immature neurons at the foregut-midgut boundary (Ganfornina Fig. 2. Tracings of midgut plexus development in the et al., 1996). Subsequently, they undergo a rapid grasshopper embryo as visualized by NO-induced cGMP- phase of migration during which the neurons cross immunoreactivity in somata and arborizations. Guts were the foregut杕idgut boundary and move in four incubated with the NO donor sodium nitroprusside (SNP) migratory pathways on the midgut surface (Fig. 2). and then immunostained with an anti-cGMP antiserum. At the completion of migration, the MG neurons Images were traced from individual preparations at the invade the space between the four migratory path- various developmental stages. Embryos are staged accord- ways and extend terminal synaptic branches on the midgut musculature. The MG neurons of the grasshopper exhibit inducible cGMP-IR throughout the phase of migration (Fig. 3a,b) and continue to show high levels of anti-cGMP staining in the phase of lateral neurite branching and the formation of terminal processes (Fig. 3c) (Haase and Bicker, 2003). When ing to the percentage of embryogenesis completed (0� 100% at hatching). Each tracing shows a dorsal view of the embryonic gut. ig, ingluvial ganglion. The midgut is marked in gray; arrows indicate two migration pathways that form the midgut nerves. When the midgut plexus acquires its mature configuration after 85% of development, the cGMP-IR decreases. This view reveals two of the four migratory pathways on top of the gut. Scale bar = 200 mm. Drawing modified from Haase and Bicker (2003). the midgut plexus acquires its mature configuration, the cGMP-IR decreases (Fig. 2). Thus, NO-induced sGC activity in MG neurons is developmentally regu- To establish a causal role of NO/cGMP signal- lated and the timing of enzyme activity coincides ling in the directed migration of the MG neurons, exactly with periods of neuronal motility as well as we used again pharmacological manipulations in axonal outgrowth. Moreover, using NADPH-diapho- whole embryo culture (Haase and Bicker, 2003). rase staining as a histochemical marker for NOS, Blocking of endogenous NO synthesis by the NOS potential sources of NO could be identified in sub- inhibitor 7NI (see Fig. 1) retards migration of the sets of non-neural cells on the midgut. MG neurons. Treatment with ODQ, a specific in- Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. Nitric Oxide Signaling During Insect Development Fig. 3. 49 Developmental expression of NO-induced cGMP- velopment. The midgut neurons (mgn) are moving pos- IR in enteric neurons. After forming a cellular packet at teriorly in a pattern of chain migration. The leading as the forgut-midgut boundary at 62% of embryonic devel- well as the following neurons of one migratory pathway opment, cGMP-IR midgut neurons began to migrate pos- show strong cGMP-IR. C: After 80% of development, some teriorly on the midgut. A: Lateral view of cGMP-IR enteric midgut neurons leave the four main migratory routes to neurons at the foregut-midgut boundary (vertical line in- spread out between the midgut nerves. During the phase dicates boundary) at 65% of development. At this stage, of lateral neurite branching and the formation of terminal cGMP-IR was present in cells of the ingluvial ganglion processes on the midgut musculature, the midgut neu- (ig), the enteric nerves, and neurons innervating the fo- rons continue to exhibit strong cGMP-IR. These micro- regut (fg). The caecae were not stained. Some of the mid- graphs were modified from Haase and Bicker (2003). Scale gut neurons migrated laterally to form a nerve ring near bars = (A) 200 the foregut-midgut boundary. B: Seventy percent of de- Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. mm; (B,C) 25 mm. 50 Bicker hibitor of sGC, also prevents the MG neuron mi- can be used as a fluorescent probe for microscopi- gration in a dose-dependent manner. In embryos cal visualization of actin filaments. Palloidin stain- treated with the specific PKG inhibitor RPcGMPS, ing of migratory MG neurons shows F-actin bundles MG neuron migration is significantly reduced. This that are mainly localized in the cellular processes effect suggests that cGMP might influence migra- but not in the cell bodies. Conversely, under con- tion via activating PKG. ditions where migration is blocked by inhibitors The disruption of MG neuron migration caused of the NO/cGMP/PKG cascade, a dense network by inhibiting NO production or cGMP synthesis of F-actin bundles spans the cell body (Haase and can be rescued by exogenous application of mem- Bicker, 2003). In all animal cells, the important brane-permeant cGMP and pharmacological stimu- second messenger molecule cyclic AMP (cAMP) lation of sGC (Fig. 1) , suggesting that in vivo a mediates protein phosphorylation via the cyclic- certain level of cGMP is necessary for MG neuron AMP-dependent protein kinase A (PKA) pathway. migration. The rescue experiments show clearly that Activation of the cAMP/PKA cascade results in an NO/cGMP signalling is essential for the regulation inhibition of MG neuron migration, which is also of neuronal migration in the developing ENS of accompanied by a cytoskeletal rearrangement. The the grasshopper. Since pharmacological inhibition corresponding type of actin bundle distribution of NOS or sGC causes no significant misrouting would be expected in stationary cells (Brown et of the MG neurons, there is no evidence for a di- al., 1999). To summarize, the experimental pertur- rectional guidance function of NO. Thus, growth bations of the signalling cascades reveal that NO/ cone motility and guidance are separate processes. cGMP signalling appears to act antagonistically to Moreover, the fact that a simple, spatially homo- cAMP/PKA signalling in the regulation of MG neu- geneous bath application of NO donors and cGMP ron motility and that elevated cGMP levels are es- to the culture medium can rescue the defect in mi- sential for the ability of migration. gration argues against a role of NO as a guidance factor for directed cell migration of the MG neu- A CO-SIGNALING PATHWAY? rons. Rather, the appearance of inducible sGC activity in the MG neurons just at the onset of Is nitric oxide the only gaseous transmitter that migration suggests that NO/cGMP signalling might regulates growth cone motility? Most likely, the be required for the initiation of migratory behav- answer is indeed NO. Carbon monoxide (CO) is ior. In primary cultured aortic smooth muscle cells, produced by heme oxygenase enzymes as a by- NO induces changes in cell shape, reorganization product during the cleavage of heme (Boehning of the actin cytoskeleton, and reduction of adhe- and Snyder, 2003) and has the potential to signal sion (Brown et al., 1999). Correspondingly, in the among other pathways via the sGC/cGMP cascade. grasshopper ENS, NO might be crucial as a per- This gas is also thought to be a member of the missive factor for the initiation and maintenance atypical signaling molecules in the nervous system of MG neuron migration. (Boehning and Synyder, 2003). Immunoreactivity Actin molecules exist either as monomers (G- to heme oxygenase 2 (HO-2), the isoform of the actin) or in polymerized helical filaments (F-ac- enzyme that generates CO in neural tissue, has tin) within the cell. Cell migration depends on been described in the stomatogastric nervous sys- forces generated by the polymerization of actin in tem of crayfish (Christie et al., 2003). The pres- cellular protrusions (Lauffenburger and Horwitz, ence of NOS and HO-2 in distinct subsets of cells 1996). These actin-rich protrusions attach to the suggests that both NO and CO may be messenger substratum and contribute to the translocation of molecules of invertebrate stomatogastric nervous the cell. A localized enrichment of actin is also es- systems. sential for the motility of neuronal growth cones. In the grasshopper embryo, the enteric neurons The fungal toxin phalloidin binds to F-actin and exhibit a transient immunoreactivity to the consti- Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. Nitric Oxide Signaling During Insect Development 51 tutive isoform HO-2 while migrating on the mid- significance of gaseous transmitters in regulating gut (Knipp and Bicker, 2006). Pharmacological cellular motility will clearly require more knowl- inhibition of HO-2 enhances midgut neuron mi- edge about how the migrating neurons integrate gration in a gain-of-function experiment. However, changes in cyclic nucleotide levels with the mo- the transduction pathway of the CO signal is not lecular guidance mechanisms for the directed yet known. Since both messengers can bind to sGC, movement. but CO is less efficient than NO to stimulate cGMP Despite the common developmental origin from formation, a competition mechanism may regu- a neuroepithelial placode in the foregut, the insect late cGMP concentration and migratory behavior enteric nervous system exhibits quite extensive varia- of the enteric neurons. tions in the detailed pattern of migration and design of neural connections (Hartenstein, 1997; DIVERSITY OF ENTERIC NERVOUS SYSTEM Ganfornina et al., 1996). For example, whereas in DEVELOPMENT IN PEST INSECTS Manduca specific sets of visceral muscle bands support migration of the enteric neurons on the mid- Using cell proliferation and other molecular gut (Copenhaver and Taghert, 1989; Copenhaver et markers, the seminal study of Ganfornina et al. al., 1996; Wright et al., 1998), no morphologically (1996) has traced the ontogenesis of the stomato- distinct muscle bands can be recognized along the gastric ganglia, nerves, and nervous plexus on fore- migratory pathways of the grasshopper embryo and midgut of the grasshopper embryo. Based on (Ganfornina et al., 1996). Instead, the migratory this neuroanatomical framework, our lab has iden- neurons move parallel to the longitudinal muscle tified NO/cGMP/PKG, cAMP/PKA, and perhaps CO bands directly on the surface of the midgut. In signal transduction pathways as regulators of neu- Manduca, different isoforms of the cell recognition ronal migration on the midgut. Surprisingly, ear- molecule fasciclin II mediate distinct aspects of the lier investigations to prove a link between NO/ migration process, such as adhesion, fasciculation, cGMP signalling and MG neuron migration in the and the promotion of motility. These results can embryo of Manduca sexta came up with a different be result (Wright et al., 1998). In Manduca develop- fasciclin II molecules on the muscle bands coin- ment, the migrating enteric neurons also show NO- ciding with the active period of cell migration, in sensitive sGC expression. The inhibition of NOS vivo manipulations using blocking antibodies, and sGC causes a reduction of terminal branch for- antisense oligodeoxynucleotides, and other types mation in a later phase of development both in of perturbation techniques that interfere with the Manduca and in the grasshopper (Wright et al., different isoforms (Wright and Copenhaver, 2000). 1998; Haase and Bicker, 2003) However, in con- Similar types of perturbation experiments have not trast to the grasshopper, inhibition of NO/cGMP been performed in the grasshopper embryo, but it signalling in Manduca does not affect neuronal mi- is evident that the expression pattern of fasciclin gration and there is no detectable NO source near II on the midgut looks quite different during cell the migrating enteric plexus cells (Wright et al., migration in the grasshopper and Manduca (Gan- 1998). These conflicting data obtained from neu- fornina et al., 1996; Wright et al., 1998; Knipp, ronal migration experiments might be due to spe- unreported data). deduced from the transient expression of cies-specific differences in the development of Considering the enormous economic damage holometabolous versus hemimetabolous insects. that locust plagues can do to pastures and crops, Differences in the experimental procedures of ani- we actually know very little about the cellular dif- mal culture or the effective concentration of the ferentiation of the enteric nervous system which pharmacological agents may have also contributed contains the pattern generating networks (Ayali, to the different outcome of the cell migration ex- 2004) that drive the locust抯 feeding machinery. The periments. A full understanding of the biological molecular identification of the guidance factors in Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. 52 Bicker economically important insect species may help to sGC blocker does not affect antennal lobe mor- unravel the detailed cellular mechanisms of sto- phology. Based on evidence from an enzyme in- matogastric nervous system formation. Perhaps, hibitor, Gibson et al. (2001) suggest that the NO these guidance cues might also provide us with effect may be mediated at least in part by ADP- novel molecular targets selective for pest insects. ribosylation of target cell proteins. To this end, comparative investigations of pest and beneficial insects are required. Clearly, ubiq- NO COORDINATES NEUROGENESIS uitous cellular signalling cascades, such as cAMP/ PKA or NO/cGMP/PKG, which are common to Both in vertebrates and invertebrates, NO is not many organisms, are useless as specific targets for only implicated in the formation of neural connec- insecticides. Therefore, our lab has also started to tivity but also in the proliferation of neuronal pre- investigate the expression of specific neuroactive cursors (Enikolopov et al., 1999; Packer et al., 2003; compounds and of cell surface molecules during Moreno-Lopez et al., 2004). In the formation of the stomatogastric nervous sys- tion of NOS results in excessive growth of body tem (Bicker et al., 2004; Stern et al., 2006; Knipp, structures whereas the ectopic expression of a NOS unreported data). transgene has the opposite effect (Kuzin et al., Drosophila , inhibi- 1996). Thus, NO signalling regulates morphogenesis by controlling the balance between cell prolif- A ROLE FOR NO IN GLIAL MIGRATION eration and cell differentiation. The antiproliferative During the development of the antennal lobe Manduca action of NO appears not to be mediated by cGMP. , the afferent Using an inducible transgene of NOS, overex- olfactory receptor neurons initially arborize in pression of genes encoding cell cycle regulatory nodular neuropile structures that are called proto- pathways, and pharmacological manipulations, the glomeruli (Tolbert et al., 2003). A specific type of mechanisms of the antiproliferative activity of NO glial cell is then required to migrate to surround have been analyzed during the formation of the these protoglomeruli and to delineate the borders compound eye (Kuzin et al., 2000). The in the olfactory system of Drosophila of the developing glomeruli. If the olfactory axons combined data argue for a role of NO in regulat- are prevented to enter the antennal lobe, glial cells ing cell divisions of the developing eye disc via do not migrate and the arborisations of sensory interaction with components of the retinoblastoma and central neurons fail to develop into the char- pathway. The notion that NO is involved in cell acteristic glomerular architecture (Tolbert et al., cycle regulation has been reinforced by studying 2003). Thus glial cell migration plays a prominent the development of the optic anlage in role in the formation of the olfactory neuropile. (Champlin and Truman, 2000). Here, proliferation Because the olfactory receptor axons express of neural precursors in the optic lobe of Manduca Manduca NOS throughout development (Gibson and Nig- is controlled by ecdysteroid levels and by local pro- horn, 2000), NO release may trigger glial cell mi- duction of NO. NADPHd staining, NOS immuno- gration. The treatment with a NOS blocker and NO cytochemistry, and a fluorescent NO-indicator scavengers disrupts the glial migration to form nor- show that cells throughout the optic anlage can mal glomerular borders, resulting in a misshapen synthesize NO. Opposing ecdysteroid stimulatory glomerular neuropile (Gibson et al., 2001). This pathways and the antiproliferatory NO pathway result suggests that NO released from the olfac- lead to a sharpening of the responsiveness to the tory receptor axons is a signal to induce the glial steroid, thereby facilitating a tight coordination migration. Interestingly, the effects of NO release between development of the different elements of do not appear to be mediated by sGC, as the glial the adult visual system. cGMP-IR During early larval stages, neuroblasts in the (Gibson and Nighorn, 2000) and application of a optic anlage undergo symmetric divisions to in- cells display no visible NO-induced Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. Nitric Oxide Signaling During Insect Development crease the number of precursor cells. NOS appears FROM DEVELOPMENTAL TIMING TO in the optic anlage when the neuroblasts shift to ADULT SYNAPTIC PLASTICITY 53 the asymmetric mode of division (Champlin and Truman, 2000). This developmental phenomenon Similar to the many physiological roles of NO may be specific for neurogenesis in the brain, since in the adult organism, the multitude of NO sig- we never could resolve distinct NADPHd staining nalling functions in development is only gradu- in the asymmetrically dividing neuroblasts of the ally becoming recognized (Enikolopov et al., 1999; grasshopper and Drosophila ventral nerve cord (e.g., Moroz, 2001; Yamamoto et al., 2003; Krumenacker Wildemann and Bicker, 1999a), whereas prolifera- and Murad, 2006). The complex task of wiring tive cell clusters of the embryonic grasshopper brains is essentially based on the specific expres- protocerebrum show NADPH-diaphorase expres- sion and recognition of extracellular guidance cues. sion (Seidel and Bicker, 2002). The outgrowing neurites do, however, also require In certain insect species, such as crickets and detailed timing information concerning when to some beetles, new neurons are also born in the advance, when to stop, and when to wait. Thus, it adult animal. In the house cricket Acheta domesticus, is not unlikely to imagine that focal release of NO adult neurogenesis occurs in the mushroom bod- may coordinate the behavior of motile growth ies (Cayre et al., 1994). These neuroanatomical cones. Since production of NO is a tightly regu- structures of the insect brain are composed of the lated process (Bredt and Snyder 1992; Garthwaite parallel projecting Kenyon cells that receive multi- and Boulton 1995), increases in cytosolic Ca modal sensory input mainly from the antennal els (M黮ler and Bicker, 1994) could provide a de- lobes and also from other regions of the nervous velopmental timing signal for the production of system (Strausfeld et al., 1998; Bicker, 2+ lev- 1999; NO. The timed generation of NO signals might Fahrbach, 2006). The mushroom bodies have been then affect cytoskeletal rearrangement to initiate implicated in olfactory memory formation, con- and maintain neurite growth. Whether localized text generalization in visual learning, and complex release of NO causes growth cone steering in vivo integrative functions (Heisenberg, 2003; Fahrbach, remains an open question. 2006). Neurogenesis in the cricket can be modu- In the developing vertebrate nervous system, evi- lated through juvenile hormone, sensory input, and dence for the involvement of NO signalling in cell NO signaling. Electrical stimulation of the anten- motility can be deduced from the transient expres- nal nerve mimicking odor sensation increases sion of NOS in migrating neurons (Santacana et al., mushroom body neurogenesis (Cayre et al., 2005). 1998; Ding et al. 2005) or from the expression of In vivo and in vitro experiments show that NOS sGC in migrating cells (Currie et al., 2006) includ- inhibition decreases, and NO donor application ing neuroblasts of the rostral migratory stream stimulates neuroblast proliferation. NADPH-d (Martinez-Guijarro et al., 2006). However, studies staining, anti-L-citrulline immunocytochemistry, using experimental perturbations of NO/cGMP sig- and in situ hybridization with a probe specific for naling remain rather scarce (but see Tanaka et al., Acheta NOS provide evidence that intrinsic mush- 1994). Intriguingly, in vitro investigations using cor- room body neurons synthesize NO. Rearing crick- tical brain slices (Polleux et al., 2000) have shown ets in an enriched sensory environment induces that an asymmetric expression of sGC controls the an upregulation of Acheta NOS mRNA, and uni- orientation of apical dendrites in cortical pyrami- lateral electrical stimulation of the antennal nerve dal neurons. Mutant mice deficient in an isoform of results in increased L-citrulline immunoreactivity PKG display defects in neocortical development that in the corresponding mushroom body (Cayre et can be ascribed to abnormal neuronal migration or al., 2005). Thus, neural activity modulates progeni- positioning (Demyanenko et al., 2005). All of these tor cell proliferation via a stimulatory effect of NO results argue for an important role of cGMP/PKG sig- on mushroom body neuroblast proliferation. nalling in the development of the cerebral cortex. Archives of Insect Biochemistry and Physiology January 2007 doi: 10.1002/arch. 54 Bicker Our embryo culture experiments show that the Bellamy TC, Garthwaite J. 2002. Pharmacology of the nitric regulation of neuronal cell migration by NO/cGMP oxide receptor, soluble guanylyl cyclase, in cerebellar cells. involves NO-induced alterations in the actin cy- Br J Pharmacol 136:95�3. toskeleton (Haase and Bicker, 2003). A reorganisation of the actin cytoskeleton does not only regulate cell motility during development. During Bentley D, O扖onnor TP. 1992. Guidance and steering of peripheral pioneer growth cones in grasshopper embryos. In: Letourneau C, Kater SB, Macagno, ER, editors. The adult synaptic plasticity, activity-dependent spine nerve growth cone. New York: Raven Press Ltd. p 265� remodeling is also driven by changes in the dy- 282. namic equilibrium between F-actin and G-actin. For example, tetanic stimulation causes a rapid shift of the actin equilibrium toward F-actin in the den- Berlot K, Goodman CS. 1984. Guidance of peripheral pioneer neurons in the grasshopper: adhesive hierarchy of epithelial and neuronal surfaces. Science 223:493�6. dritic spines of rat hippocampal neurons (Okamoto et al., 2004). Release of NO has been implicated as Bicker G. 1999. Histochemistry of classical neurotransmit- retrograde messengers associated with long-term ters in antennal lobes and mushroom bodies of the hon- potentiation in the hippocampus (Hawkins et al., eybee. Microsc Res Tech 45:174�3. 1998). The NO/sGC/PKG signalling cascade and proteins that regulate the actin cytoskeleton contribute to the aggregation of synaptic proteins as a Bicker G. 2001. Nitric oxide: an unconventional messenger in the nervous system of an orthopteroid insect. Arch Insect Biochem Physiol 48:100�0. form of structural plasticity in long-lasting potentiation (Wang et al., 2005). Thus, NO may affect neurotransmission by acting on components of the synaptic cytoskeleton. Since insects also display Bicker G, Schmachtenberg O. 1997. Cytochemical evidence for nitric oxide/cyclic GMP signal transmission in the visual system of the locust. Eur J Neurosci 9:189�3. striking examples of structural plasticity during the Bicker G, Schmachtenberg O, De Vente J. 1996. The nitric development and functioning of their nervous sys- oxide/cyclic GMP messenger system in olfactory pathways tems (e.g., Fahrbach, 2006), it may be useful to of the locust brain. Eur J Neurosci 8:2635�43. search for contributions of NO signalling to the underlying changes in the neuronal cytoskeleton. Bicker G, Schmachtenberg O, De Vente J. 1997. Geometric considerations of nitric oxide-cyclic GMP signalling in the glomerular neuropil of the locust antennal lobe. Proc R ACKNOWLEDGMENTS This review is based on a symposium talk at the XXII International Congress of Entomology, Brisbane, Australia. 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