FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development.
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.
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN Oxford, UK.
Elena
E
Seiradake
Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
Daniel
D
del Toro
Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University Munich, Großhaderner Str. 2, 82152 Planegg-Martinsried, Germany.
Daniel
D
Nagel
Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, Saarstr. 21, 55122 Mainz, Germany.
Florian
F
Cop
Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, Saarstr. 21, 55122 Mainz, Germany.
Ricarda
R
Härtl
Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
Tobias
T
Ruff
Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany.
Gönül
G
Seyit-Bremer
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN Oxford, UK.
Karl
K
Harlos
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN Oxford, UK.
Ellen Clare
EC
Border
Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, Saarstr. 21, 55122 Mainz, Germany.
Amparo
A
Acker-Palmer
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN Oxford, UK. Electronic address: yvonne@strubi.ox.ac.uk.
E Yvonne
EY
Jones
Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address: rklein@neuro.mpg.de.
Rüdiger
R
Klein
D000818:Animals; D002448:Cell Adhesion; D018360:Crystallography, X-Ray / Q000379:methods; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D051381:Rats
D006025:Glycosaminoglycans; D008565:Membrane Proteins; C007858:glucuronyl glucosamine glycan sulfate