FLRT Structure: Balancing Repulsion and Cell Adhesion in Cortical and Vascular Development

DOI: 10.1016/j.neuron.2014.10.008
PMID: 25374360

Authors: Elena Seiradake (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Daniel Del toro (Max Planck Institute of Neurobiology) , Daniel Nagel (Max Planck Institute of Neurobiology) , Florian Cop (Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt) , Ricarda Härtl (Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt) , Tobias Ruff (Max Planck Institute of Neurobiology) , Gönül Seyit-bremer (Max Planck Institute of Neurobiology) , Karl Harlos (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Ellen clare Border (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Amparo Acker-palmer (Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt) , Edith Jones (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Rüdiger Klein (Max Planck Institute of Neurobiology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Neuron , VOL 84 (2) , PAGES 370 - 385

State: Published (Approved)
Published: October 2014
Diamond Proposal Number(s): 8423

Abstract: FLRTs are broadly expressed proteins with the unique property of acting as homophilic cell adhesion molecules and as heterophilic repulsive ligands of Unc5/Netrin receptors. How these functions direct cell behavior and the molecular mechanisms involved remain largely unclear. Here we use X-ray crystallography to reveal the distinct structural bases for FLRT-mediated cell adhesion and repulsion in neurons. We apply this knowledge to elucidate FLRT functions during cortical development. We show that FLRTs regulate both the radial migration of pyramidal neurons, as well as their tangential spread. Mechanistically, radial migration is controlled by repulsive FLRT2-Unc5D interactions, while spatial organization in the tangential axis involves adhesive FLRT-FLRT interactions. Further, we show that the fundamental mechanisms of FLRT adhesion and repulsion are conserved between neurons and vascular endothelial cells. Our results reveal FLRTs as powerful guidance factors with structurally encoded repulsive and adhesive surfaces.

Journal Keywords: Cell; Crystallography; X-Ray; Glycosaminoglycans; Humans; Membrane; Mice; Mutation; Neurons; Rats

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

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