Following Directions from the Retina to the Brain
Authors: Thomas A. Ray, Jeremy N. Kay
Journal: Neuron (2015)

Different types of retinal ganglion cells (RGCs) project to distinct brain targets. In this issue of Neuron, Osterhout et al., 2015Osterhout J.A. Stafford B.K. Nguyen P.L. Yoshihara Y. Huberman A.D. Neuron. 2015; 86 (this issue): 985-999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar and Sun et al., 2015Sun L.O. Brady C.M. Cahill H. Al-Khindi T. Sakuta H. Dhande O.S. Noda M. Huberman A.D. Nathans J. Kolodkin A.L. Neuron. 2015; 86 (this issue): 971-984Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar identify how direction-selective RGC axons match with their targets and the consequences for visual function when targeting is impaired. Different types of retinal ganglion cells (RGCs) project to distinct brain targets. In this issue of Neuron, Osterhout et al., 2015Osterhout J.A. Stafford B.K. Nguyen P.L. Yoshihara Y. Huberman A.D. Neuron. 2015; 86 (this issue): 985-999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar and Sun et al., 2015Sun L.O. Brady C.M. Cahill H. Al-Khindi T. Sakuta H. Dhande O.S. Noda M. Huberman A.D. Nathans J. Kolodkin A.L. Neuron. 2015; 86 (this issue): 971-984Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar identify how direction-selective RGC axons match with their targets and the consequences for visual function when targeting is impaired. Like most sensory systems, the vertebrate visual system is organized into parallel channels that process distinct aspects of the sensory stimulus. These channels arise in the retina, where local circuitry isolates features of the visual scene such as changes in light level, color, or motion in particular directions. These features are then reported to the brain through the firing patterns of ∼30 retinal ganglion cell (RGC) types, each of which constitutes a distinct information channel (Sanes and Masland, 2015Sanes J.R. Masland R.H. Annu. Rev. Neurosci. 2015; 38: 221-246Crossref PubMed Scopus (457) Google Scholar). What happens to these channels when they reach the brain remains somewhat murky. Most RGCs project along the optic tract to the lateral geniculate nucleus and/or the superior colliculus, but there are dozens of additional brain regions that receive RGC inputs—46 in mouse (Morin and Studholme, 2014Morin L.P. Studholme K.M. J. Comp. Neurol. 2014; 522: 3733-3753Crossref PubMed Scopus (125) Google Scholar). Presumably, if the retina goes to the trouble of parsing information into distinct RGC channels, they should project to distinct targets. For the limited number of RGC types that have been analyzed, we know that their projections are indeed quite specific: they target distinct sublayers of the geniculate and colliculus, and they project to distinct subsets of the minor retinorecipient targets (Baier, 2013Baier H. Annu. Rev. Cell Dev. Biol. 2013; 29: 385-416Crossref PubMed Scopus (40) Google Scholar, Dhande and Huberman, 2014Dhande O.S. Huberman A.D. Curr. Opin. Neurobiol. 2014; 24: 133-142Crossref PubMed Scopus (119) Google Scholar). This finding raises the question: what are the molecular mechanisms that determine the specificity of RGC projections? These mechanisms are important because they ensure that each channel of visual information is delivered to a brain region that can make use of it. In this issue of Neuron, two papers tackle this question, uncovering key molecular cues for wiring one particular visual channel, and demonstrating the perceptual consequences when this channel is not wired correctly (Osterhout et al., 2015Osterhout J.A. Stafford B.K. Nguyen P.L. Yoshihara Y. Huberman A.D. Neuron. 2015; 86 (this issue): 985-999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, Sun et al., 2015Sun L.O. Brady C.M. Cahill H. Al-Khindi T. Sakuta H. Dhande O.S. Noda M. Huberman A.D. Nathans J. Kolodkin A.L. Neuron. 2015; 86 (this issue): 971-984Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). The visual pathway addressed in these two papers has a specialized role in detecting full-field motion for the purpose of image stabilization: when the head or body moves, the entire visual image will shift on the retina. Motion, detected by the retina or the inner ear, drives two reflexes—the optokinetic and the vestibulo-ocular reflexes—that produce compensatory eye movements to keep the image stable and clear. The RGCs that detect image motion for the optokinetic reflex were discovered in the rabbit in the 1960s and have subsequently been identified in most vertebrates (Dhande and Huberman, 2014Dhande O.S. Huberman A.D. Curr. Opin. Neurobiol. 2014; 24: 133-142Crossref PubMed Scopus (119) Google Scholar). These cells respond best to light increments and to directional motion, so they are known as ON direction-selective (DS) RGCs. The ON DS RGCs comprise three distinct cell types, each of which prefers to fire to motion in a particular direction (Figure 1A). Their axons project to a group of brain nuclei known as the accessory optic system (AOS), so called because it arises from a RGC axon pathway distinct from the main optic tract. A subset of ON DS cells also project through the main optic tract and synapse in a region known as the nucleus of the optic tract (NOT). Remarkably, each of the three ON DS cell types projects to a different AOS region (Figure 1B): cells that prefer up and down motion project to separate subdivisions of the region known as the medial terminal nucleuls (MTN), while cells that prefer forward motion project to the dorsal terminal nucleus (DTN). Forward cells also target the NOT, which is nearly contiguous with the DTN. All three nuclei show visual responses that match the directional tuning of the RGCs that project there, and all three project to cerebellar and oculomotor circuits involved in executing reflexive eye movements. Moreover, lesion studies in rabbits and birds show direction-specific defects in optokinetic reflexes when AOS nuclei are damaged (Simpson, 1984Simpson J.I. Annu. Rev. Neurosci. 1984; 7: 13-41Crossref PubMed Google Scholar). Thus, information about the direction of motion, relayed by these three nuclei, is critical for driving eye movements in the appropriate direction. How do RGCs that prefer particular directions select the correct brain target? To address this question, the authors of these two papers use mouse lines that express GFP selectively in ON DS RGCs. This allows them not only to see axons in the brain, but to assess expression of candidate molecules by RGCs. Sun et al., 2015Sun L.O. Brady C.M. Cahill H. Al-Khindi T. Sakuta H. Dhande O.S. Noda M. Huberman A.D. Nathans J. Kolodkin A.L. Neuron. 2015; 86 (this issue): 971-984Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar find that Sema6A, a transmembrane Semaphorin with many known roles in axon patterning, is expressed by a subset of ON DS RGCs that project to the MTN. Knockout of the Sema6a gene prevents ON DS RGC axons from innervating the MTN—their axons pause outside it but cannot enter. Subsequently, perhaps due to the lack of a target-derived survival cue, the RGCs die. PlexinA2 and PlexinA4 are well-characterized receptors for Sema6A. Sun et al., 2015Sun L.O. Brady C.M. Cahill H. Al-Khindi T. Sakuta H. Dhande O.S. Noda M. Huberman A.D. Nathans J. Kolodkin A.L. Neuron. 2015; 86 (this issue): 971-984Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar find that they are expressed in the MTN and that they are required for its innervation, just like Sema6A. In this system, however, the usual receptor and ligand roles are unexpectedly reversed: PlexinA2 and PlexinA4 turn out to be ligands that can attract RGC axons in a Sema6A-dependent manner. ON DS RGCs therefore appear to use Sema6A as a receptor to detect Plexin ligand in the MTN, thereby stimulating axon entry. While there is precedent for so-called “reverse” signaling by transmembrane Semaphorins (Toyofuku et al., 2004Toyofuku T. Zhang H. Kumanogoh A. Takegahara N. Yabuki M. Harada K. Hori M. Kikutani H. Nat. Cell Biol. 2004; 6: 1204-1211Crossref PubMed Scopus (166) Google Scholar), this mechanism is still quite surprising. It will be interesting to learn the signaling pathways through which Sema6A controls axon growth. So far we have considered only the MTN, the nucleus that encodes vertical motion—what about the horizontal motion system? The DTN and NOT are innervated through disparate cellular mechanisms—the DTN via dedicated AOS axons, and the NOT by collateral branches from the main optic tract (Figure 1B). We might therefore expect disparate molecular mechanisms to be involved as well. Indeed, in mutants lacking PlexinA2 and PlexinA4, the NOT is normal, while innervation of the DTN is largely absent. Thus, Plexin ligands are required for innervation of both vertical (MTN) and horizontal (DTN) AOS nuclei, but they do not influence the main optic tract. In Sema6A mutants, DTN innervation is impaired but not absent, suggesting that the forward-preferring ON DS cells use multiple Plexin receptors to target the DTN. This additional receptor remains to be identified. How, then, do ON DS neurons target their axons to the NOT? Osterhout et al., 2015Osterhout J.A. Stafford B.K. Nguyen P.L. Yoshihara Y. Huberman A.D. Neuron. 2015; 86 (this issue): 985-999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar find that Contactin 4, a cell-surface protein of the immunoglobulin superfamily, is selectively expressed by RGC axons that innervate the NOT. Contactin (Cntn) molecules are involved in a variety of adhesive cell-cell interactions, including targeting of axons within the olfactory bulb and retina (Kaneko-Goto et al., 2008Kaneko-Goto T. Yoshihara S. Miyazaki H. Yoshihara Y. Neuron. 2008; 57: 834-846Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Yamagata and Sanes, 2012Yamagata M. Sanes J.R. J. Neurosci. 2012; 32: 14402-14414Crossref PubMed Scopus (94) Google Scholar), making Cntn4 an excellent candidate to mediate axon-target matching. Osterhout et al., 2015Osterhout J.A. Stafford B.K. Nguyen P.L. Yoshihara Y. Huberman A.D. Neuron. 2015; 86 (this issue): 985-999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar find that innervation of the NOT is severely reduced in Cntn4 mutants, due to a reduced propensity of optic tract axons to send collateral branches into it. Moreover, misexpression of Cntn4 in random RGCs is sufficient to promote their collateral branching into the NOT. Osterhout et al., 2015Osterhout J.A. Stafford B.K. Nguyen P.L. Yoshihara Y. Huberman A.D. Neuron. 2015; 86 (this issue): 985-999Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar further show that the activity of Cntn4 requires interactions with amyloid precursor protein (APP)—better known for its role in Alzheimer’s disease than in brain development—which is co-expressed on RGC axons. The two molecules may form a co-receptor complex that initiates axon branching upon binding to a ligand, still unidentified, that resides in the NOT. Together, the results in these two papers take us a long way toward understanding the mechanisms that target all three types of ON DS RGCs to their brain targets. The molecular details of these mechanisms are unusual and reveal new players in the wiring of brain circuits. But perhaps the most satisfying aspect of these two papers is that they are able to demonstrate the consequences for visual perception when ON DS RGC wiring is perturbed. To do this, the authors measure the optokinetic reflex (OKR) in their mutant mice. Head-fixed animals are shown full-field stimuli moving in various directions, which provokes eye movements that track the stimulus. If the reflex is impaired, tracking eye movements are reduced or absent. All the mutants showed at least mild OKR deficits for all motion directions, but the strength of the phenotypes differed for horizontal and vertical motion: Sema6a mutants, which lack innervation of the MTN, showed essentially no vertical OKR. Cntn4 mutant mice, which have faulty innervation of the NOT, were much more severely impaired for horizontal OKR. And double mutants lacking PlexinA2 and PlexinA4, which lack innervation of both AOS nuclei, were severely impaired in both vertical and horizontal OKR. The finding in Cntn4 mutant mice is particularly striking, because the authors show that in the absence of innervation by ON DS cells, a different direction-selective RGC type fills the NOT void and projects there instead. However, these RGCs are clearly not able to provide the right kind of directional information to this reflexive circuit, as shown by the behavioral deficit. These papers open up a variety of fascinating new questions. First, on the molecular side: what receptor guides ON DS axons to the DTN? What is the NOT ligand that stimulates collateral branching, and how does it interact with the Cntn4-APP complex? Does APP have broader roles in wiring of brain circuits? The mechanisms by which Cntn4 and APP influence the cell biology of developing neurons will be particularly interesting to explore. This is because Cntn-family genes, including Cntn4, are associated with a number of psychiatric diseases, but the underlying pathobiology is still unclear (Zuko et al., 2013Zuko A. Kleijer K.T.E. Oguro-Ando A. Kas M.J.H. van Daalen E. van der Zwaag B. Burbach J.P.H. Eur. J. Pharmacol. 2013; 719: 63-74Crossref PubMed Scopus (79) Google Scholar). At the circuit level, one intriguing question is why mild deficits in detecting the “off-target” direction were observed. The NOT and AOS nuclei are interconnected (Simpson, 1984Simpson J.I. Annu. Rev. Neurosci. 1984; 7: 13-41Crossref PubMed Google Scholar), raising the possibility that interactions between them might contribute to the calculation of motion direction. Another possibility arises from the observation that some AOS neurons are not unidirectional in their preferred directions. Such cells show rotational motion sensitivity that might map onto the rotational coordinate system of the three semicircular canals in the inner ear (Simpson, 1984Simpson J.I. Annu. Rev. Neurosci. 1984; 7: 13-41Crossref PubMed Google Scholar). If such a cell lost RGC innervation, the behavioral consequences might be more complex than simply losing one axis of motion detection. Finally, these studies suggest that it should be possible, using a similar developmental-genetic approach, to trace other retinal output channels into the brain and learn what the visual system is doing with that information. Such studies hold the promise of revealing how the brain uses elementary retinal inputs to construct our visual world. Functional Assembly of Accessory Optic System Circuitry Critical for Compensatory Eye MovementsSun et al.NeuronMay 7, 2015In BriefThe molecular mechanisms that direct the development of the accessory optic system (AOS) are poorly understood. In this study, Sun et al. show that PlexA2/A4-Sema6A reverse signaling regulates the functional assembly of AOS connections critical for compensatory eye movements. Full-Text PDF Open ArchiveContactin-4 Mediates Axon-Target Specificity and Functional Development of the Accessory Optic SystemOsterhout et al.NeuronMay 7, 2015In BriefIn this study, Osterhout et al. discovered molecular mechanisms essential for wiring up the neurons that drive slip-compensating eye movements. These findings shed light on the mechanistic underpinnings of visual circuit assembly in a behaviorally relevant context. Full-Text PDF Open Archive