A Retino-retinal Projection Guided by Unc5c Emerged in Species with Retinal Waves

Abstract

Summary The existence of axons extending from one retina to the other has been reported during perinatal development in different vertebrates. However, it has been thought that these axons are either a labeling artifact or misprojections. Here, we show unequivocally that a small subset of retinal ganglion cells (RGCs) project to the opposite retina and that the guidance receptor Unc5c, expressed in the retinal region where the retinal-retinal (R-R) RGCs are located, is necessary and sufficient to guide axons to the opposite retina. In addition, Netrin1, an Unc5c ligand, is expressed in the ventral diencephalon in a pattern that is consistent with impeding the growth of Unc5c-positive retinal axons into the brain. We also have generated a mathematical model to explore the formation of retinotopic maps in the presence and absence of a functional connection between both eyes. This model predicts that an R-R connection is required for the bilateral coordination of axonal refinement in species where refinement depends upon spontaneous retinal waves. Consistent with this idea, the retinal expression of Unc5c correlates with the existence and size of an R-R projection in different species and with the extent of axonal refinement in visual targets. These findings demonstrate that active guidance drives the formation of the R-R projection and suggest an important role for these projections in visual mapping to ensure congruent bilateral refinement.

Interhemispheric connections between olfactory bulbs improve odor detection

“…Beyond the olfactory system, the present findings add to the existing literature describing the anatomical organization and functional role of interhemispheric connections in sensory processing [9,10]. Evidence of interhemispheric connectivity between early topographic maps in other sensory modalities than olfaction is scarce: a direct interhemispheric connection between retinae, mediated by contralaterally projecting ganglion cells, was recently identified in vertebrates [76]. This connection is only present at perinatal stages and might underlie the synchronization of bilateral retinal waves during development.…”

Interhemispheric connections between olfactory bulbs improve odor detection

“…Beyond the olfactory system, the present findings add to the existing literature describing the anatomical organization and functional role of interhemispheric connections in sensory processing [9,10]. Evidence of interhemispheric connectivity between early topographic maps in other sensory modalities than olfaction is scarce: a direct interhemispheric connection between retinae, mediated by contralaterally projecting ganglion cells, was recently identified in vertebrates [76]. This connection is only present at perinatal stages and might underlie the synchronization of bilateral retinal waves during development.…”

Isl1 Controls Axon Pathfinding of Retinal Ganglion Cells in the Binocular Visual Pathway

“…4 A ). Unc5c (UNC5C) is an axon guidance receptor required for the growth of retino-retinal axons and its expression is repressed by ZIC2 in ipsilateral RGCs (Murcia-Belmonte et al, 2019; Fernández-Nogales et al, 2022). Sncg (SNCG, γ -synuclein) is a transcriptional target of POU4F1 and required for midline crossing of contralateral RGCs (Fernández-Nogales et al, 2022).…”

Human Retinal Ganglion Cells Respond to Evolutionarily Conserved Chemotropic Cues for Intra Retinal Guidance and Regeneration

“…In the “Axon Guidance” GO term, among the downregulated genes in response to blocking of Netrin-1/DCC interactions included DCC along with other Netrin-1 receptors, UNC5C and UNC5D , co-expressed in many neurons including RGCs ( Fig. 11D )(Lai Wing Sun et al, 2011, Murcia-Belmonte et al, 2019). This result is informative as positive influence of Netrin-1/DCC interactions on Netrin-1 receptors gene expression may offer a mechanistic explanation for the diverse cellular effects of Netrin-1 on human RGCs.…”

Interhemispheric connections between olfactory bulbs improve odor detection

“…Beyond the olfactory system, the present findings add to the existing literature describing the anatomical organization and functional role of interhemispheric connections in sensory processing [9,10]. Evidence of interhemispheric connectivity between early topographic maps in other sensory modalities than olfaction is scarce: a direct interhemispheric connection between retinae, mediated by contralaterally projecting ganglion cells, was recently identified in vertebrates [76]. This connection is only present at perinatal stages and might underlie the synchronization of bilateral retinal waves during development.…”

Isl1 Controls Axon Pathfinding of Retinal Ganglion Cells in the Binocular Visual Pathway

“…4 A ). Unc5c (UNC5C) is an axon guidance receptor required for the growth of retino-retinal axons and its expression is repressed by ZIC2 in ipsilateral RGCs (Murcia-Belmonte et al, 2019; Fernández-Nogales et al, 2022). Sncg (SNCG, γ -synuclein) is a transcriptional target of POU4F1 and required for midline crossing of contralateral RGCs (Fernández-Nogales et al, 2022).…”

Human Retinal Ganglion Cells Respond to Evolutionarily Conserved Chemotropic Cues for Intra Retinal Guidance and Regeneration

“…In the “Axon Guidance” GO term, among the downregulated genes in response to blocking of Netrin-1/DCC interactions included DCC along with other Netrin-1 receptors, UNC5C and UNC5D , co-expressed in many neurons including RGCs ( Fig. 11D )(Lai Wing Sun et al, 2011, Murcia-Belmonte et al, 2019). This result is informative as positive influence of Netrin-1/DCC interactions on Netrin-1 receptors gene expression may offer a mechanistic explanation for the diverse cellular effects of Netrin-1 on human RGCs.…”

Interhemispheric connections between olfactory bulbs improve odor detection

“…Beyond the olfactory system, the present findings add to the existing literature describing the anatomical organization and functional role of interhemispheric connections in sensory processing [9,10]. Evidence of interhemispheric connectivity between early topographic maps in other sensory modalities than olfaction is scarce: a direct interhemispheric connection between retinae, mediated by contralaterally projecting ganglion cells, was recently identified in vertebrates [76]. This connection is only present at perinatal stages and might underlie the synchronization of bilateral retinal waves during development.…”

Isl1 Controls Axon Pathfinding of Retinal Ganglion Cells in the Binocular Visual Pathway

“…4 A ). Unc5c (UNC5C) is an axon guidance receptor required for the growth of retino-retinal axons and its expression is repressed by ZIC2 in ipsilateral RGCs (Murcia-Belmonte et al, 2019; Fernández-Nogales et al, 2022). Sncg (SNCG, γ -synuclein) is a transcriptional target of POU4F1 and required for midline crossing of contralateral RGCs (Fernández-Nogales et al, 2022).…”

Human Retinal Ganglion Cells Respond to Evolutionarily Conserved Chemotropic Cues for Intra Retinal Guidance and Regeneration

“…In the “Axon Guidance” GO term, among the downregulated genes in response to blocking of Netrin-1/DCC interactions included DCC along with other Netrin-1 receptors, UNC5C and UNC5D , co-expressed in many neurons including RGCs ( Fig. 11D )(Lai Wing Sun et al, 2011, Murcia-Belmonte et al, 2019). This result is informative as positive influence of Netrin-1/DCC interactions on Netrin-1 receptors gene expression may offer a mechanistic explanation for the diverse cellular effects of Netrin-1 on human RGCs.…”