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The role of classic morphogens such as Sonic hedgehog (Shh) as axon guidance cues has been reported in a variety of vertebrate organisms (Charron and Tessier-Lavigne [2005] Development 132:2251-2262). In this work, we provide the first evidence that Xenopus sonic hedgehog (Xshh) signaling is involved in guiding retinal ganglion cell (RGC) axons along the optic tract. Xshh is expressed in the brain during retinal axon extension, adjacent to these axons in the ventraldiencephalon. Retinal axons themselves express Patched 1 and Smoothened co-receptors during RGCaxon growth. Blocking Shh signaling causes abnormal ventral pathfinding, and targeting errors at the optic tectum. Misexpression of exogenous N-Shh peptide in vivo also causes pathfinding errors. Retinal axons grown in culture respond to N-Shh in a dose-dependent manner, either by decreasing extension at lower concentrations, or retracting axons in the presence of higher doses. These data suggest that Shh signaling is required for normal RGCaxon pathfinding and tectal targeting in the developing visual system of Xenopus. We propose that Shh serves as a ventral optic tract repellent that helps to define the caudal boundary for retinal axons in the diencephalon, and that this signaling is also required for initial target recognition at the optic tectum.
Figure 1. Xshh expression in the developing brain. A–C: Lateral views of Xshh mRNA expression (blue) in stage 32, 34, and 38 embryonic brains, respectively. D:Xshh is found at the level of the midbrain in a transverse section of a stage 38 Xenopus embryo. Dotted red line denotes the presumptive location of the optic tract. E: A ventral view of HRP-labeled retinal axons (brown), along with Xshh expression (blue) in a stage 38 brain, at the optic chiasm. F: A lateral view of the same co-labeled brain, along the optic tract, with the white arrow at RGC axons, midway across the diencephalon. Unless otherwise noted, in all appropriate figures, dorsal is to the top. fp, floor plate; no, notochord; nt, neural tube; oc, optic chiasm; ot, optic tectum. Scale bar in D = 100 μm, and in F = 40 μm.
Figure 2. XPtc1 and XSmo co-receptor expression in RGCs. Ptc1 and Smo expression is observed in the RGC layer and the retinal pigment epithelium (RPE) of sectioned retinas from stage 39 embryos (A, B, respectively) as compared to a negative control (C). D, E: Individual cultured RGCs are identified by neurofilament associated antigen (NAA) immunoreactivity. These retinal cells are also shown to express both Ptc1 (G) and Smo (H). F, I: No appreciable staining is detected in negative controls. rgcl: retinal ganglion cell layer; rpe, retinal pigment epithelium. Scale bar in D = 10 μm.
Figure 3. Abnormal RGCaxon extension after Shh disruption. Changes in the width of retinal projections at the ventral optic tract in an untreated embryo (A) and a cyclopamine-treated sample (B) are shown. C: Cyclopamine treatment also causes defasiculation of retinal axons. D: The transverse section of a control sample reveals normal RGC axonal projections (arrows) just below the lateral surface neuroepidermis. E: After cyclopamine treatment, RGC axons project inwards (arrows). F: A lateral view of a control sample shows normal RGCaxon extension along the entire optic tract. G: After cyclopamine treatment, there is spreading of retinal axons at the tectum. A closer view of the tectum in an untreated control (H) versus a cyclopamine-treated embryo (I) shows abnormal targeting (arrows). The tectal boundary is outlined by the dotted white lines in H and I. Scale bar in H = 10 μm.
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