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Cell-Cell Interactions During the Migration of an Identified Commissural Growth Cone in the Embryonic Grasshopper

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Cell-Cell Interactions During the Migration of an Identified Commissural Growth Cone in the Embryonic Grasshopper The Journal of Neuroscience, January 1993, 13(l): 115-126 Cell-Cell Interactions during the Migration of an Identified Commissural Growth Cone in the Embryonic Grasshopper Paul 2. Myers and Michael J. Bastiani Department of Biology, University of Utah, Salt Lake City, Utah 84112 One of the fascicles of the posterior commissure of the em- interactions, such as haptotaxis or passivesteering to regionsof bryonic grasshopper is pioneered by an individually identi- increasedadhesivity (Letoumeau, 1982) but there are a number fiable neuron named Ql. 01 initially grows along a longi- of reports of discrete, dynamic reactions to specific contacts, tudinal pathway established by another pioneer neuron, MPl, such as growth cone inhibition (Kapfhammer and Raper, 1987; and then crosses to the midline, where it meets and fascicu- Cox et al., 1990; Raper and Kapthammer, 1990)or rapid changes lates with the axon of the contralateral 01. The Ql growth in intracellular ionic concentrations (Kater et al., 1988) that can cone follows the contralateral Ql axon to the contralateral generatenovel growth cone behaviors. longitudinal pathway, where it then fasciculates with axons There are alsoreports in the literature that describeimportant of the MPl/dMP2 fascicle. In this work, we have identified interactions at a distance. For instance,diffusable growth factors a small set of early neurons that Ql could use as guidance affect the outgrowth of peripheral sensory fibers (Levi-Montal- cues while negotiating its way along a specific and stereo- cini and Angeletti, 1968; Gundersenand Barret, 1979)and neu- typed pathway to the midline. Furthermore, we have ob- rons of the CNS (Thoenen et al., 1987). The axons of commis- served characteristic morphological changes in the Ql growth sural neuronscan be induced to extend toward isolatedportions cone that could indicate responses to changing adhesivity of the floorplate by diffusible tropic factors (Tessier-Lavigneet in the substrates it contacts. We have also quantified the al., 1988). Commissural neurons represent a particularly inter- pattern of dye coupling between neurons in this system. esting problem in growth cone navigation, becauseit is difficult Most of the neurons to which 01 becomes coupled retain a to explain their behavior in terms of exclusively local adhesive strong, consistent pattern of dye coupling that shows no interactions. Commissuralgrowth conesmust reject the closest, recognizable variation at times when growth cones are mak- ipsilateral target and grow acrossthe midline to select a more ing pathway decisions. However, we have found one clear remote, but presumably equivalent, contralateral target. Pos- instance of transient, site-specific dye coupling between the sible mechanismsfor this initial disregardofthe ipsilateral target Ql growth cone and the ipsilateral MPl soma. include physical constraints on turning by growth cones(Katz, The timing and pattern of dye coupling in this system sug- 1985; Lefcourt and Bentley, 1989) simple unavailability due to gest that dye coupling may play a role in synchronizing the timing differences, timing-dependent variations in preferences initiation of axon outgrowth among a small population of driven by intrinsic factors such as maturation, or location-de- neurons. Although dye coupling may not play a direct role pendent respecificationofa growth cone’stargets by informative in neuronal pathfinding, it may exert a profound indirect in- interactions en route (Bovolenta and Dodd, 1990). fluence on neuronal interactions by regulating the timing of One approach to identifying potentially important interac- axon outgrowth. tions for pathfinding is to observe the changing behavior of [Key words: growth cone, dye-coupling, commissure, growth conesand thereby deduce the identity of environmental grasshopper, pathfinding, filopodia, confocal microscopy] cues recognized by the cell. Growth coneshave been observed to make characteristic changesin their rate of growth (Raper et Current thinking about the mechanismsthat guide axon out- al., 1983; Myers et al., 1986) or size and shape (Tosney and growth is dominated by the idea that growth cones are led to Landmesser, 1985; Bovolenta and Mason, 1987) when they their targets by a seriesof local interactions. Growth conesmay reach specific choice points. Sites of preferential adhesionalso contact particular guidepost cells and use them as navigational can be implied by a nonrandom, stereotyped disposition of cues(Bentley and Keshishian, 1982; Taghert et al., 1982; Bentley filopodia (Taghert et al., 1982; Bastiani et al., 1984; Bray and and Caudy, 1983a), or follow specific adhesive substrates(Bent- Chapman, 1985). ley and Caudy, 1983b; Bastiani et al., 1984; Blair and Palka, The presenceof important cell-cell interactions also may be 1989) or regional disparities (Letourneau, 1975; Hammarback revealed by the appearanceof temporally and spatially specific et al., 1985; Burmeister and Goldberg, 1988). The local inter- patterns of dye coupling, mediated by gap junctions. Very early actions often can be thought of as simple mechanical or physical in embryonic development, all cells tend to be coupled together by gap junctions; the systematic loss of junctional communi- Received Oct. 25, 1991; revised Jul. 13, 1992; accepted Jul. 15, 1992. cation between embryonic tissuesduring histogenesismay play We thank Rommy van Bemhardi, Ellen Carpenter, Rolf Karlstrom, and Elaine a role in restricting a cell’s fate, and the retention of coupling Seaver for their discussion and helpful criticism of the manuscript. This work was within a tissue may help maintain a common program of de- supported by 5T32 CA09602 and NS08656 to P.Z.M. and NS25378 and a McKnight Foundation award to M.J.B. velopment for those cells (Guthrie et al., 1988; Guthrie and Correspondence should be addressed to Dr. Paul Z. Myers at the above address. Gilula, 1989). The embryonic nervous system is a unique tissue Copyright 0 1993 Society for Neuroscience 0270-6474/93/ 130 1 I5- 12$05.00/O in that its cells become uncoupled from one another early in 116 Myers and Bastiani * Commissural Growth Cone interactions their differentiation (Caveney, 1985) but then secondarily re- Dye coupling. We injected the cells Q I, MP I, and posterior corner couple to other neurons during the course of their outgrowth cell (pCC) (n = 249) with dye at 3&35% of development, and measured (Lo Presti et al., 1974; Bentley and Keshishian, 1982; Raper the time required for the dye to pass from the injected neuron to other cells. To minimize photodamage, we observed cells only briefly once and Goodman, 1982; Eisen et al., 1989). Like their counterparts every I5 set for the first minute after the injection, once every 30 set in other tissues, gap junctions in the developing nervous system for the next 2 min, and once every 60 set thereafter. Under this regimen, could play a role in determination, maintenance, or differenti- the cells remained apparently healthy (i.e., there was no blehhing or ation of tissue-specific properties (Caveney, 1985); their cor- deterioration of fine processes) for up to I5 min. Injections were not analyzed if they failed to meet two criteria: (1) relation with contacts with guidepost neurons (Bentley and the injected cell had to be sufficiently differentiated that it had uncoupled Keshishian, 1982) and with changes in growth cone motility from most of its neighbors, and (2) the injected cell had to exhibit (Kater et al., 1988) suggests that gap-junctional communication coupling to at least one other specific cell. Eight percent of the injections may also play a role in pathfinding. However, dye coupling is were rejected because they failed to meet the first criterion. All of these a widespread phenomenon, and gives little evidence of speci- cases occurred early, at 3 1% of embryogenesis or earlier, and produced a widespread diffusion of dye that we interpret to indicate that the ficity; attempts to disrupt the pattern of gap-junctional com- injection was made prior to the normal uncoupling and differentiation munication by ablating individual elements in the network have of the cell. Another 13% failed to meet the second criterion. Each of shown no effect on pathfinding (Eisen et al., 1989); and not all the three cell types has an adjacent neuron to which it is strongly coupled: growing neurons dye couple to other cells along their path of 01 is paired with 02. uCC with an anterior comer cell (aCC). and MPI with two neurons;d’MP2 and vMP2. If dye failed to pass from the outgrowth (Holt, 1989). In principle, the formation ofgap junc- injected cell to its neighbor, we assumed that the injection procedure tions that allow small cytoplasmic factors to travel freely be- had traumatized the cell and forced an artificial uncoupling. tween cells should be a significant opportunity for cell-cell com- Ofthe successful injections, we measured the latency, or time required munication, but the relevance of this communication during for an observable quantity of dye to pass from the injected cell to any neurogenesis is not well understood. other cells to which it was dye coupled. One serious difficulty with any study of dye coupling is that the phenomenon is extremely fragile and In this work, we characterize in detail a particularly simple variable; the process of penetrating the membrane to introduce the dye system of neurons that has substantial advantages for dissecting can be sufficiently traumatic to trigger partial or complete uncoupling. the various interactions involved in guiding a commissural neu- We cannot eliminate all experimental artifacts from this kind of study, ron to its target. The commissural neuron Ql of the embryonic but we offer two observations that validate our measurements. First, all the cells studied couple strongly to an adjacent and usually related grasshopper highlights the complications of commissural out- cell, providing an internal control. Second, some of our numbers speak growth, yet is part of a very small subset of mutually interacting for the consistency and delicacy ofour technique (Table I). We observed neurons that are amenable to experimental manipulation.
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