Assembly and repair of eye-to-brain connections.

Vision is the sense humans rely on most to navigate the world and survive. A tremendous amount of research has focused on understanding the neural circuits for vision and the developmental mechanisms that establish them. The eye-to-brain, or 'retinofugal' pathway remains a particularly important model in these contexts because it is essential for sight, its overt anatomical features relate to distinct functional attributes and those features develop in a tractable sequence. Much progress has been made in understanding the growth of retinal axons out of the eye, their selection of targets in the brain, the development of laminar and cell type-specific connectivity within those targets, and also dendritic connectivity within the retina itself. Moreover, because the retinofugal pathway is prone to degeneration in many common blinding diseases, understanding the cellular and molecular mechanisms that establish connectivity early in life stands to provide valuable insights into approaches that re-wire this pathway after damage or loss. Here we review recent progress in understanding the development of retinofugal pathways and how this information is important for improving visual circuit regeneration.

Dynamic expression of p75NTR and Lingo-1 during development of mouse retinofugal pathway.

Our previous studies showed interaction of Nogo at the midline with its receptor (NgR) on optic axons plays a role in axon divergence at the mouse optic chiasm. Since NgR lacks a cytoplasmic domain, it needs transmembrane receptor partners for signal transduction. In this study, we examined whether the co-receptors of NgR, low-affinity neurotrophic receptor (p75NTR) and Lingo-1, are localized on axons in the mouse optic pathway. In the retina, p75NTR and Lingo-1 were observed on neuroepithelial cells at E13 and later on the retinal ganglion cells at E14 and E15. At the optic disc, p75NTR was observed on the retinal axons, whereas Lingo-1 was found on glial processes surrounding the axon fascicles. Both p75NTR and Lingo-1 were found on axons in the optic stalk, optic chiasm and optic tract. Furthermore, a transient expression of Lingo-1 was observed on the SSEA-1 positive chiasmatic neurons at E13, but not at later developmental stages. The presence of p75NTR and Lingo-1 on optic axons provides further supports to the contribution of Nogo/NgR signaling in axon divergence at the mouse optic chiasm.

Visual Experience-Dependent Expression of Fn14 Is Required for Retinogeniculate Refinement.

Sensory experience influences the establishment of neural connectivity through molecular mechanisms that remain unclear. Here, we employ single-nucleus RNA sequencing to investigate the contribution of sensory-driven gene expression to synaptic refinement in the dorsal lateral geniculate nucleus of the thalamus, a region of the brain that processes visual information. We find that visual experience induces the expression of the cytokine receptor Fn14 in excitatory thalamocortical neurons. By combining electrophysiological and structural techniques, we show that Fn14 is dispensable for early phases of refinement mediated by spontaneous activity but that Fn14 is essential for refinement during a later, experience-dependent period of development. Refinement deficits in mice lacking Fn14 are associated with functionally weaker and structurally smaller retinogeniculate inputs, indicating that Fn14 mediates both functional and anatomical rearrangements in response to sensory experience. These findings identify Fn14 as a molecular link between sensory-driven gene expression and vision-sensitive refinement in the brain.