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The First Retinal Axon Growth in the Mouse Optic Chiasm: Axon Patterning and the Cellular Environment

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The First Retinal Axon Growth in the Mouse Optic Chiasm: Axon Patterning and the Cellular Environment The Journal of Neuroscience, October 1995, 15(10): 6369-6402 The First Retinal Axon Growth in the Mouse Optic Chiasm: Axon Patterning and the Cellular Environment Riva C. Marcus and Carol A. Mason Departments of Pathology, and Anatomy and Cell Biology, Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032 The retinofugal pathway is a useful model for axon guicl- indicating that boundariesof geneexpression may influence pat- ante because fibers from each eye project to targets on terns of axon growth (Figdor and Stern, 1993; Wilson et al., both sides of the brain. Studies using static and real time 1993; Macdonald et al., 1994), little information exists on cells analyses in mice at Ei5-17 demonstrated that uncrossed and moleculesresiding within axonal paths in the brain, in par- axons from ventrotemporal retina diverge from crossed ax- ticular with respectto the first growing axons (Silver, 1984; Sil- ons in the optic chiasm, where specialized resident cells ver and Rutishauser,1984; Wilson and Easter, 1991). may direct divergence. Other studies, however, suggest In mammals,the retina sendsboth crossedand uncrossedpro- that pioneering uncrossed retinal axons derive from a dif- jections to visual targets in the brain (Polyak, 1957; Guillery, ferent retinal region, take a different course, and enter the 1982). Crossedand uncrossedretinal ganglion cells in the adult ipsilateral optic tract independent of fiber-fiber interac- visual pathway derive from defined regionsof the retina (Drager, tions. We examine these differences by dye-labeling the 1985; Godementet al., 1987b; Colello and Guillery, 1990; Sre- earliest optic axons and immunocytochemically identifying tavan, 1990). Dye-labeling of axons in static and living mouse cells in their path. tissue at El.%17 reveals that all optic axons, regardlessof des- The first optic axons arising from dorsocentral retina, en- tination, first grow toward the midline. Growth coneson crossed ter the diencephalon at E12.5. All axons initially grow cau- axons crossthe midline, whereasthose on uncrossedaxons be- dally, lateral to a radial glial palisade. In contrast to later come complex and turn away from the midline back toward the growing axons, early uncrossed axons enter the ipsilateral ipsilateral optic tract (Godementet al., 1987b; Sretavan, 1990). optic tract directly. Crossed axons enter the glial palisade A cellular specializationis centered around the chiasmaticmid- and course medially, then anteriorly, in a pathway corre- line (Marcus et al., 1995). This specializationconsists of a pal- sponding to the border of an early neuronal population that isade of radial glia intersected by a narrow midline raphe of expresses SSEA-1, CD44, and f3-tubulin. Axon patterning cells arising from a band of early neuronsposterior to the optic occurs independent of fiber-fiber interactions from both chiasm. Retinal axon divergence occurs within this specializa- eyes, as the first uncrossed axons enter the optic tract be- tion, consistentwith the hypothesisthat divergence cues are lo- fore crossed ones from the opposite eye. These analyses, cated in this zone. in conjunction with our previous studies during the prin- While thesestudies demonstrate that the adult pattern of optic cipal period of retinal axon growth in the diencephalon, axon projections arises during embryonic development, other suggest that the adult visual projection arises from age- observationssuggest that the earliest axonal growth pattern dif- dependent variations in the types and relative contribution fers from the adult pattern in three respects.First, the earliest of cues along the path through the emerging optic chiasm. uncrossedaxons arise from dorsocentraland not ventrotemporal [Key words: optic chiasm, axon guidance, midline, radial retina (Godement et al., 1987b; Colello and Guillery, 1990; glia, SEA-l, divergence] Chan et al., 1993; Baker and Colello, 1994). Second,early un- crossedaxons appear to grow directly into the ipsilateral optic The advent of improved tract tracing techniques and antigen tract, without first growing toward the midline (Silver, 1984; markers of early axons has heralded a resurgencein studies on Godement et al., 1987b; Colello and Guillery, 1990). Third, in- the establishmentof axonal pathways in the vertebrate brain teractions between axons from both eyes, apparently critical for (Chitnis and Kuwada, 1990; Wilson et al., 1990; Easter et al., the uncrossedpath of ventrotemporal retinal axons (Godement 1993, 1994; Chedotal et al., 1995). Aside from recent reports et al., 1987a; Chan and Guillery, 1993), may be unnecessaryfor pathways taken by earlier axons (Sretavan and Reichardt, 1993). Received Apr. 3, 1995; revised June 5, 1995; accepted June 7, 1995. We expand these observationsby providing details on the pat- We thank Drs. Jane Dodd, Mary Morrison, and Pierre Godement for criti- tern of early retinal axon growth with respect to the cellular cally reading the manuscript and Drs. Steve Easter, Ray Guillery, David Sre- tavan, and Li-Chong Wang for stimulating and insightful discussions. We also architecture of the nascent chiasm. thank Drs. Jane Dodd. Tonv Frankfurter. Jean-Paul Misson. and Charles Un- Our results demonstratethat distinct mechanismsinfluence derhill for supplying us with antibodies. &pport was provided by NRSA F32 EY06510 (R.C.M.), NIH Grant NS27615 (Jacob Javits Award, C.A.M.), and optic axon trajectory during early and later development. This Program Project NS30532. work provides a framework for analyzing how patterns of gene Correspondence should be addressed to Dr. Carol Mason, Department of expressionin the retina (Kaprielian and Patterson, 1994; Savitt Pathology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, Room 14-509, New York, NY 10032. et al., 1995) and forebrain (Figdor and Stern, 1993; Puellesand Copyright 0 1995 Society for Neuroscience 0270.6474/95/156389-14$05.00/O Rubenstein,1993; Hatini et al., 1994; Tole and Patterson,1995) 6390 Marcus and Mason * Establishment of the Mouse Optic Chiasm posterior fi ..‘.‘.‘..,,,, ..: :. 7,. ,,,,...;,q frontal anterior sections Wholemount of the ventral diencephalon El 2.5 - El 3.5 (Horizontal view) Figure 1. Methods. DiI and DiO were applied to the optic nerve head in the right and left eyes, respectively, of fixed embryos between El25 and E13.5. The brain, including the optic stalks, was dissected free, and the region overlying the third ventricle removed. Preparations were viewed both as wholemounts and in frontal sections. Double-labeling of photoconverted, dye-labeled preparations was performed as detailed in Materials and Methods. The dottedline indicates the location of the third ventricle. relate to retinal topographic specification, axonal patterning, and J.-P Misson and V. Caviness (Massachusetts General Hospital). MAb regional identity in the brain. RC2 specifically stains immature astrocytes in the mouse CNS (Misson et al., 1988) and a midline palisade of radial glia in the optic chiasm Materials and Methods of E15-El7 mice (Marcus et al., 1995). Monoclonal antibody 480-1.1 (mouse IgM) was obtained from the All experiments were carried out with C57B1/6J mice from a timed- Developmental Studies Hybridoma Bank (Solter and Knowles, 1978). pregnancy breeding colony in this department. The time of conception This antibody recognizes stage-specific embryonic antigen 1 (SSEA-l), was considered midnight before the day on which a plug was found, expressed by early embryonic stem cells and human granulocytes and noon the following day embryonic day 0.5 (E0.5). Because de- (Knowles et al., 1982), by the floor plate and radial glia in the spinal velopmental rates vary between pups from different mothers and with- cord (Dodd and Jessell, 1985; Dodd, personal communication), and by in individual litters (see Easter et al., 1993), embryos were grouped a group of cells in the ventral diencephalon in mice at E15-El7 (Marcus according to the degree of retinal axon growth rather than absolute et al., 1995). age. CD44 is a T-cell antigen found in the immune system (Denning et Pregnant mothers containing embryos between the ages of El 1.5- al., 1990; Tanaka et al., 1993) and in the developing optic chiasm (Sre- E13.5 were anesthetized with a mixture of ketamine and xylazine, and tavan, 1993; Sretavan et al., 1994). CD44-positive cells were visualized the embryos removed one at a time by caesarean section. Embryos by the KM201 antibody (rat IgG) generously provided by Dr. C. Un- older than El25 were perfused transcardially with 4% paraformal- derhill (Georgetown). dehyde in 0.1 M phosphate buffer. Younger embryos were fixed by Neurons were visualized using the TuJl antibody (mouse IgG), gen- immersion in the same fixative. After fixation for four hours at room erously provided by Dr. A. Frankfurter (University of Virgina). Mono- temperature or overnight at 4°C the tissue was washed and stored in clonal antibody TuJl recognizes an antigen present on neuron-specific phosphate buffer. class III B-tubulin (Lee et al., 1990) and appears to recognize all early axons and neuronal cell bodies in the mouse CNS (Easter et al., 1993). Dil labeling of retinal axons in Jixed tissue Zmmunostaining.Immunostaining was performed on both sections Crystals of DiI (l,l’-dioctadecyl-3,3,3’,3’-tetramethylindocaocyanine and wholemounts (Fig. 1). Wholemounts with and without DiI-photo- perchlorate) and DiO (3,3’-dioctadecyloxacarbocyanine perchlorate) converted axons were incubated in blocking buffer [O.l M phosphate were applied to the optic nerve head of the right and left eyes, respec- buffer containing 5% normal goat serum (NGS) and 0.5% Triton X-100 tively. Dye was applied to the optic nerve head to ensure labeling of (Sigma)] for 1 hr to block nonspecific binding. The preparations were the maximum number of optic axons. The tissue was stored in the dark then incubated in the primary antibody diluted in blocking buffer for 1 at room temperature in phosphate buffer containing sodium azide for d, followed by six 30 min washes in phosphate buffer. Following 1 hour 5-7 d to allow transport of the dye.
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