Spatiotemporal coordination of Slit-Robo repulsion and neurturin-Gfrα attraction guides multipolar migration during retinal lamination

TL;DR

This study shows how repulsive and attractive signals guide neurons to their correct positions in the developing retina, ensuring proper brain structure.

Contribution

The study identifies a spatiotemporal coordination mechanism between repulsive and attractive signaling during neuronal migration in the retina.

Findings

Repulsive Slit1b/2-Robo2 signaling initiates apical migration of horizontal cells out of the amacrine cell layer.

Attractive neurturin-Gfrα1/2-Ret signaling fine-tunes the final positioning of horizontal cells beneath photoreceptors.

Disruption of these pathways leads to improper neuronal positioning and impaired retinal circuitry.

Abstract

Multipolar migration is a conserved neuronal migration mode in the developing brain, enabling emerging neurons to navigate in crowded environments and reach precise laminar positions. Yet, how these cells interpret external cues to guide their migration is not fully understood. We investigate this question using retinal horizontal cells as a model. Combining transcriptomics, targeted CRISPR screening, and live imaging, we reveal the spatiotemporal guidance system underlying horizontal cell lamination: repulsive Slit1b/2-Robo2 signaling in the amacrine cell layer initiates apical horizontal cell migration, while attractive neurturin-Gfrα1/2 signaling from photoreceptors fine-tunes final positioning beneath the photoreceptor layer. Disruption of these pathways causes basal retention of horizontal cells, highlighting the importance of spatially coordinated signaling for proper lamination and functional retinal circuitry. Our results uncover how positional signals and tissue architecture cooperate to achieve neuronal migration precision, a principle likely relevant across the developing central nervous system.

•RNA-seq-guided CRISPR screen reveals guidance cues involved in horizontal cell positioning•Repulsive Slit1b/2-Robo2 signaling steers horizontal cells out of the amacrine cells•Neurturin-Gfrα1/2-Ret attraction ensures horizontal cell positioning beneath photoreceptors•Interference with these cues impairs neuronal patterning in the vertebrate retina

RNA-seq-guided CRISPR screen reveals guidance cues involved in horizontal cell positioning

Repulsive Slit1b/2-Robo2 signaling steers horizontal cells out of the amacrine cells

Neurturin-Gfrα1/2-Ret attraction ensures horizontal cell positioning beneath photoreceptors

Interference with these cues impairs neuronal patterning in the vertebrate retina

Lehtimäki et al. reveal how repulsive Slit1b/2-Robo2 and attractive neurturin-Gfrα1/2-Ret signaling jointly coordinate multipolar migration of horizontal cells through crowded, scaffold-free environments of the vertebrate retina. This work was enabled by sophisticated transcriptomics analysis, targeted F0 CRISPR screening, and 3D fixed and live imaging.

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