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Spatiotemporal coordination of Slit-Robo repulsion and neurturin-Gfrα attraction guides multipolar migration during
Jaakko I Lehtimäki1, Jingtao Lilue2, Margarida R Cruz3
1Instituto Gulbenkian de Ciência (IGC), 2780-156 Oeiras, Portugal; Gulbenkian Institute for Molecular Medicine (GIMM), 2780-156 Oeiras, Portugal; InFLAMES Research Flagship Center, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
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.
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