SummaryFLRTs 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.
Highlights d Crystal structures reveal binding site for Latrophilin on the Teneurin YD shell d A ternary Latrophilin-Teneurin-FLRT complex forms in vitro and in vivo d Latrophilin controls cortical migration by binding to Teneurins and FLRTs d Latrophilin elicits repulsion of cortical cell bodies/small neurites but not axons
The present work shows a significant enhancement of the photoelectrochemical water-splitting performance of anodic TiO(2) nanotube layers grown on low concentration (0.01-0.2 at% Ru) Ti-Ru alloys. Under optimized preparation conditions (0.05 at% Ru, 450 °C annealing) the water splitting rate of the oxide tubes could be 6-fold increased. Moreover, the beneficial effect is very stable with illumination time; this is in contrast to other typical doping approaches of TiO(2).
The folding of the mammalian cerebral cortex into sulci and gyri is thought to be favored by the amplification of basal progenitor cells and their tangential migration. Here, we provide a molecular mechanism for the role of migration in this process by showing that changes in intercellular adhesion of migrating cortical neurons result in cortical folding. Mice with deletions of FLRT1 and FLRT3 adhesion molecules develop macroscopic sulci with preserved layered organization and radial glial morphology. Cortex folding in these mutants does not require progenitor cell amplification but is dependent on changes in neuron migration. Analyses and simulations suggest that sulcus formation in the absence of FLRT1/3 results from reduced intercellular adhesion, increased neuron migration, and clustering in the cortical plate. Notably, FLRT1/3 expression is low in the human cortex and in future sulcus areas of ferrets, suggesting that intercellular adhesion is a key regulator of cortical folding across species.
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