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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
Discipline Tags:
Technical Tags: