RESEARCH HIGHLIGHTS
© Mary Evans Picture Library/Alamy
Nature Reviews Neuroscience | AOP, published online 28 May 2015; doi:10.1038/nrn3979
A X O N G U I DA N C E
Setting up for seeing in slow motion
RGC innervation of the NOT in App–/– mice was less dense than in wildtype mice
In response to slow motion of the visual field, the accessory optic system (AOS) mediates the optokinetic reflex (OKR), whereby the eyes move to compensate for visual motion. The AOS comprises the medial terminal nucleus (MTN) and the nucleus of the optic tract (NOT), which are innervated by retinal ganglion cells (RGCs) that are selective for vertical and horizontal motion, respectively. However, it is not known how the direction-selective RGC–AOS circuits develop. Now, two studies in Neuron shed light on some of the molecular factors that are necessary for RGC axon targeting and OKR function in mice. In the first study, Sun et al. used various cell-labelling techniques to show that semaphorin 6A (SEMA6A) is expressed in MTN-projecting RGCs. Intriguingly, although RGCs projected to and arrived at the MTN of Sema6a–/– mice during embryonic stages, by postnatal day 1 (P1) there were fewer RGC projections in the MTN of Sema6a–/– mice than in wildtype mice. These data suggest that SEMA6A is necessary for successful targeting and maintenance of RGC axons in the MTN. Plexin A2 (PLXNA2) and PLXNA4 were previously known to function as SEMA6A receptors. In this study, the authors found that both plexins were expressed in the MTN — but not in RGCs. RGC
projections were not seen in the MTN of mice lacking PLXNA2 and PLXNA4. Whereas wild-type retinal explants extended axonal projections preferentially onto stripes bearing PLXNA2 and PLXNA4 ectodomains, axons from retinal explants from Sema6a–/– mice showed no such preference for plexins, indicating that in this system SEMA6A functions as a receptor, responding to plexins to mediate axon targeting. Finally, Sun et al. found that vertical OKR responses to slow-moving gratings were abrogated in Sema6a–/– mice and in Plxna2–/–;Plxna4–/– mice. Thus, SEMA6A, PLXNA2 and PLXNA4 are all required for normal vertical OKR. In the second study, Osterhout et al. found that contactin 4 (CNTN4) was expressed in the axons of RGCs in the NOT during early postnatal development. Moreover, in Cntn4+/– and Cntn4–/– mice, the NOT was less densely innervated by RGC projections. Using sparse in vivo electroporation of RGCs with plasmids encoding tdTomato, the authors showed that the arbors of these NOT-projecting RGCs in Cntn4–/– mice were less complex and had a lower surface area than did NOT-projecting RGCs in wild-type mice. RGCs that ectopically expressed CNTN4 from P1 to P8 were more likely to innervate the NOT than were tdTomato-expressing RGCs, which
NATURE REVIEWS | NEUROSCIENCE
were more likely to travel through the NOT without arborizing. Together, these results suggest that CNTN4 biases RGC arborization in the NOT. Amyloid precursor protein (APP) is a binding partner of CNTN4, and immunostaining revealed that APP is expressed in most NOT RGC axons. RGC innervation of the NOT in App–/– mice was less dense than in wild-type mice, and App–/– RGCs that ectopically expressed CNTN4 and App–/– RGCs that expressed tdTomato were equally unlikely to innervate the NOT, suggesting that APP is necessary for the biasing effects of CNTN4 on RGC–NOT projections. In addition, OKR responses to horizontally (and, to a lesser extent, vertically) drifting gratings were reduced in Cntn4–/– mice, indicating that CNTN4 is important for the OKR response. Together, these studies show how interactions among SEMA6A, PLXNA2 and PLXNA4, and between CNTN4 and APP, are crucial for the normal development of the circuits underlying vertical and horizontal OKRs, respectively. Natasha Bray ORIGINAL RESEARCH PAPERS Sun, L. O. et al. Functional assembly of accessory optic system circuitry critical for compensatory eye movements. Neuron http://dx.doi.org/10.1016/j. neuron.2015.03.064 (2015) | Osterhout, J. A. et al. Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron http://dx.doi.org/10.1016/j. neuron.2015.04.005 (2015)
VOLUME 16 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
© Mary Evans Picture Library/Alamy
Nature Reviews Neuroscience | AOP, published online 28 May 2015; doi:10.1038/nrn3979
A X O N G U I DA N C E
Setting up for seeing in slow motion
RGC innervation of the NOT in App–/– mice was less dense than in wildtype mice
In response to slow motion of the visual field, the accessory optic system (AOS) mediates the optokinetic reflex (OKR), whereby the eyes move to compensate for visual motion. The AOS comprises the medial terminal nucleus (MTN) and the nucleus of the optic tract (NOT), which are innervated by retinal ganglion cells (RGCs) that are selective for vertical and horizontal motion, respectively. However, it is not known how the direction-selective RGC–AOS circuits develop. Now, two studies in Neuron shed light on some of the molecular factors that are necessary for RGC axon targeting and OKR function in mice. In the first study, Sun et al. used various cell-labelling techniques to show that semaphorin 6A (SEMA6A) is expressed in MTN-projecting RGCs. Intriguingly, although RGCs projected to and arrived at the MTN of Sema6a–/– mice during embryonic stages, by postnatal day 1 (P1) there were fewer RGC projections in the MTN of Sema6a–/– mice than in wildtype mice. These data suggest that SEMA6A is necessary for successful targeting and maintenance of RGC axons in the MTN. Plexin A2 (PLXNA2) and PLXNA4 were previously known to function as SEMA6A receptors. In this study, the authors found that both plexins were expressed in the MTN — but not in RGCs. RGC
projections were not seen in the MTN of mice lacking PLXNA2 and PLXNA4. Whereas wild-type retinal explants extended axonal projections preferentially onto stripes bearing PLXNA2 and PLXNA4 ectodomains, axons from retinal explants from Sema6a–/– mice showed no such preference for plexins, indicating that in this system SEMA6A functions as a receptor, responding to plexins to mediate axon targeting. Finally, Sun et al. found that vertical OKR responses to slow-moving gratings were abrogated in Sema6a–/– mice and in Plxna2–/–;Plxna4–/– mice. Thus, SEMA6A, PLXNA2 and PLXNA4 are all required for normal vertical OKR. In the second study, Osterhout et al. found that contactin 4 (CNTN4) was expressed in the axons of RGCs in the NOT during early postnatal development. Moreover, in Cntn4+/– and Cntn4–/– mice, the NOT was less densely innervated by RGC projections. Using sparse in vivo electroporation of RGCs with plasmids encoding tdTomato, the authors showed that the arbors of these NOT-projecting RGCs in Cntn4–/– mice were less complex and had a lower surface area than did NOT-projecting RGCs in wild-type mice. RGCs that ectopically expressed CNTN4 from P1 to P8 were more likely to innervate the NOT than were tdTomato-expressing RGCs, which
NATURE REVIEWS | NEUROSCIENCE
were more likely to travel through the NOT without arborizing. Together, these results suggest that CNTN4 biases RGC arborization in the NOT. Amyloid precursor protein (APP) is a binding partner of CNTN4, and immunostaining revealed that APP is expressed in most NOT RGC axons. RGC innervation of the NOT in App–/– mice was less dense than in wild-type mice, and App–/– RGCs that ectopically expressed CNTN4 and App–/– RGCs that expressed tdTomato were equally unlikely to innervate the NOT, suggesting that APP is necessary for the biasing effects of CNTN4 on RGC–NOT projections. In addition, OKR responses to horizontally (and, to a lesser extent, vertically) drifting gratings were reduced in Cntn4–/– mice, indicating that CNTN4 is important for the OKR response. Together, these studies show how interactions among SEMA6A, PLXNA2 and PLXNA4, and between CNTN4 and APP, are crucial for the normal development of the circuits underlying vertical and horizontal OKRs, respectively. Natasha Bray ORIGINAL RESEARCH PAPERS Sun, L. O. et al. Functional assembly of accessory optic system circuitry critical for compensatory eye movements. Neuron http://dx.doi.org/10.1016/j. neuron.2015.03.064 (2015) | Osterhout, J. A. et al. Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron http://dx.doi.org/10.1016/j. neuron.2015.04.005 (2015)
VOLUME 16 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
