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Glia Dictate Pioneer Axon Trajectories in the Drosophila Embryonic CNS

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Glia Dictate Pioneer Axon Trajectories in the Drosophila Embryonic CNS Development 127, 393-402 (2000) 393 Printed in Great Britain © The Company of Biologists Limited 2000 DEV1479 Glia dictate pioneer axon trajectories in the Drosophila embryonic CNS Alicia Hidalgo* and Gwendolen E. Booth Neurodevelopment Group, Department of Genetics, University of Cambridge, UK *Author for correspondence (e-mail: [email protected]) Accepted 19 November; published on WWW 20 December 1999 SUMMARY Whereas considerable progress has been made in extending growth cones is rich in neuronal cell bodies and understanding the molecular mechanisms of axon guidance glia, and also in long processes from both these cell types. across the midline, it is still unclear how the axonal Interactions between neurons, glia and their long processes trajectories of longitudinal pioneer neurons, which never orient extending growth cones. Secondly, glia direct the cross the midline, are established. Here we show that fasciculation and defasciculation of axons, which pattern longitudinal glia of the embryonic Drosophila CNS direct the pioneer pathways. Together these events are essential formation of pioneer axon pathways. By ablation and for the selective fasciculation of follower axons along the analysis of glial cells missing mutants, we demonstrate that longitudinal pathways. glia are required for two kinds of processes. Firstly, glia are required for growth cone guidance, although this requirement is not absolute. We show that the route of Key words: Glia, Axon guidance, Ablation, gcm, CNS, Drosophila INTRODUCTION Over recent years, most work on guidance has focused on understanding the control of midline crossing by growth cones Axons extend to form intricate and stereotyped trajectories. (Tessier-Lavigne and Goodman, 1996; Thomas, 1998; Tear, Local and long-range cues are thought to aid pathfinding by 1999). In Drosophila, the ventral nerve cord of the embryonic the first axons to trace a pathway (pioneer axons; Bate, 1976). CNS consists of longitudinal connectives, with two As pioneer growth cones navigate they ‘decide’ whether to commissures across the midline linking the connectives in each follow along or move away from a given direction. Such segment (Goodman and Doe, 1992). Most interneurons cross decisions are made at stereotyped choice points and may reflect the midline once and fasciculate with pioneer axons to grow a combination of local cues and signals from the target. Once along the longitudinal pathways up to the brain. Both attractive the primary axonal trajectories are established, follower and repulsive signals are secreted by midline cells to control neurons project growth cones, which fasciculate with pioneer midline crossing by axons (Dickson, 1998; Tessier-Lavigne axons. When a pathway is shared by neurons with ultimately and Goodman, 1996; Thomas, 1998; Tear, 1999). These long- different trajectories, follower axons must ‘decide’ which range signals are evolutionarily conserved, implying that route to take, consequently defasciculating from sister axons. midline cells play a fundamental role in controlling axon It is believed that each neuron is ‘able’ to read cues with crossing. Longitudinal pioneer axons, however, are such precision as to execute multiple fasciculation and characterised by their lack of midline crossing. The role of glia defasciculation decisions in an environment heavily dense in in the establishment of these longitudinal pathways remains axons, to finally make correct contacts with its target unclear. (Goodman et al., 1984; Goodman and Shatz, 1993; Tessier- Thus far, the evidence does not favour a role for glia in the Lavigne and Goodman, 1996). guidance of longitudinal axons. CNS glia in some ways It has long been believed that glia preform the pathways that resembling oligodendrocytes, called here longitudinal glia, axons will follow (Silver et al., 1982; Singer et al., 1979) and enwrap the longitudinal axons (interface glia in Ito et al., there is evidence from vertebrates and grasshopper suggesting 1995). The longitudinal glia originate from a lateral glioblast that glia can guide growth cones and can also prompt which divides while migrating towards the midline (Jacobs et fasciculation and defasciculation of axons at choice points al., 1989; Schmidt et al., 1997). EM studies had suggested that (Auld, 1999; Pfrieger and Barres, 1995). In grasshopper, glia form a prepattern of guidepost cells for the growth cones ablation of the segment boundary cell prevents exit of the aCC to follow (Jacobs and Goodman, 1989a). However, the axon from the CNS (Bastiani and Goodman, 1986). However, progression of pioneer growth cone extension relative to glial in the CNS it is still uncertain whether glia aid pathfinding or migration patterns remains unknown. Mutations and ablation not (Auld, 1999; Pfrieger and Barres, 1995). of glia have been used to study the role of glia in guidance. 394 A. Hidalgo and G. E. Booth Glia were ablated by means of the GAL4 system with glia- MATERIALS AND METHODS specific lines available at the time (Hidalgo et al., 1995). However, in the only case where glia were ablated prior to Fly stocks growth cone extension, the MP2 and SP1 neurons were also (1) Wild type: Canton-S; (2) glial cells missing mutants: ablated, obscuring any involvement of glia in guidance. In the gcm∆P1/CyOlacZ (Jones et al., 1995); (3) synthetic glial GAL4 driver: remaining cases, the glia were ablated at a time following w; s-gcmGAL4 15.1, insertion on the X (Booth et al., 2000); (4) w; growth cone extension, so the question of pioneer growth cone UAS-RicinA/CyOen11 lacZ (Hidalgo et al., 1995): CyOen11lacZ guidance could not be addressed. The effects of several drives lacZ expression in stripes in the embryo, in the expression mutations on longitudinal tract formation have been analysed pattern of the wingless gene; (5) double GAL4 line driving expression in glia and MP2: w; s-gcmGAL4 211/CyOlacZ; 15J2/15J2 (for a but, because these genes are involved in midline or neuronal description of 15J2, see Hidalgo and Brand, 1997). development, their effects are not direct (Auld, 1999; Jacobs, 1993). In the more specific repo glial mutants, however, Ablations longitudinal tracts form (Halter et al., 1995). Mutants for the Ablation of glia was carried out with the GAL4 system (Brand and gene glial cells missing (gcm) lack all glia, which are Perrimon, 1993). The line s-gcmGAL4 151 was engineered by fusing transformed into neurons (Hosoya et al., 1995; Jones et al., a synthetic enhancer with 11 repeats of the consensus binding 1995; Pfrieger and Barres, 1995; Vincent et al., 1996). sequence for Gcm upstream of GAL4 (see Booth et al., 2000). Line Embryos lacking gcm can lack all longitudinal tracts. However, s-gcm GAL4 151 drives expression in the glioblast, progenitor of the longitudinal axon tracts can also form, leading to the longitudinal glia, and its progeny, and in other glial classes in a mosaic conclusion that glia play no essential role in guidance (see fashion (Booth et al., 2000). This line also drives sporadic expression in some macrophages and in a reduced number of neurons, mainly references above). However, the transformation to neuronal from stage 16. These neurons are not the pioneer neurons. The fate is incomplete, since in the PNS chordotonal organs only combined stock s-gcmGAL4 211/CyOlacZ; 15J2/15J2 drives GAL4 15-30% of hemisegments have all glia transformed to neurons expression both in the longitudinal glia (in 1-3 hemisegments per (Hosoya et al., 1995; Jones et al., 1995). Furthermore, the embryo) and the dMP2 and vMP2 neurons (in most segments). Only transformed cells may retain some glial features, since they embryos in which ablation had taken place were analysed. Embryos migrate, divide and reach the neuropile as normal glia do in which ablation had not taken place were identified by the (Hosoya et al., 1995; Vincent et al., 1996). Remarkably, the expression of lacZ from the reporter balancer chromosomes, which number of β-gal-positive cells in gcmPlacZ mutants is the same was visualised with anti-β-gal antibodies. Hemisegments where glial as that of glia in wild type, indicating that the glioblast lineage ablation was verified by staining with anti-Repo were analysed. In has not been altered (Hosoya et al., 1995). Furthermore, ablations with sgcmGAL4 151, neighbouring or adjacent non-ablated hemisegments in the same embryos were used as controls for normal because lacZ-expressing transformed cells are found along the trajectories at the same stage. axonal pathways of the CNS (Hosoya et al., 1995; Vincent et al., 1996), it is also conceivable that they might still provide Immunocytochemistry novel cues that axons are also able to follow (Pfrieger and Antibody stainings were carried out following standard procedures, Barres, 1995). Consequently, gcm mutations do not simply using the Vectastain Elite kit from Vector Labs, and NiCl was used correspond to lack of glia but to a novel composition of the for colour intensification when necessary. Anti-Repo was used at ventral nerve cord. 1:300 (gift of Travers); anti-Heartless at 1:1000 (gift of Hosono); fasII Longitudinal pathways are pioneered by pCC, MP1, dMP2 at 1:5 (gift of Goodman); 22c10 at 1:10 (gift of Patel). For rhodamine- and vMP2, which extend in pairs in opposite directions (Bate phalloidin staining, embryos were fixed in 80% ethanol, incubated and Grunewald, 1981; Bastiani et al., 1986; Jacobs and first with 22c10 and subsequently with rhodamine-phalloidin (gift of Martin-Bermudo) for 40 minutes together with FITC anti-mouse.
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