Spatiotemporal coordination of Slit-Robo repulsion and neurturin-Gfrα attraction guides multipolar migration during retinal lamination
: Lehtimäki, Jaakko; Lilue, Jingtao; Cruz, Margarida R.; Del Rosario, Mario; Nerli, Elisa; Henriques, Ricardo; Norden, Caren
: 2026
Cell Reports
: 116948
: 45
: 2
: 2211-1247
: 2211-1247
DOI: https://doi.org/10.1016/j.celrep.2026.116948
: https://doi.org/10.1016/j.celrep.2026.116948
: https://research.utu.fi/converis/portal/detail/Publication/515795460
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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We thank all members of the Cell Biology of Tissue Morphogenesis laboratory for lively project discussion. Joa o Coelho, Renata Cunha, and Ricardo Ribeiro gave cloning support, and Mariana Gil helped with transplantation. We acknowledge the Flow cytometry, Bioimaging, Genomic, Bioinformatics, His-topathology, and Aquatic facilities at the Gulbenkian Institute for Molecular Medicine (GIMM, formerly IGC) for technical support. We further thank Rui Hou and Allistair Forest for assistance with updating the NATMI connectome for zebrafish. Guillaume Jacquemet and Julien Vermot are thanked for constructive comments on the manuscript. We are grateful to Eyleen Goh, Jan Kaslin, and Paolo Panza for sharing the pCS2-Robo2, pDEST-ptf1a:Gal4, and UAS:ActinCB-TagGFP2 constructs, respectively. C.N. discloses support for the research of this work from European Research Council consolidator grant (H2020 ERC-2018-CoG-81904) . J.I.L. was additionally supported for the research of this work from a Fundac , a o para a Cie ncia e a Tecnologia CEEC (2023.07063.CEECIND/CP2854/CT0002) . R.H. and M.D.R. were sup-ported by the ERC under the European Union's Horizon 2020 research and innovation program (grant agreement no. 101001332) (to R.H.) .
