Abstract
Netrins, a family of laminin-related molecules, have been proposed to act as guidance cues either during nervous system development or the establishment of the vascular system. This was clearly demonstrated for netrin-1 via its interaction with the receptors DCC and UNC5s. However, mainly based on shared homologies with netrin-1, netrin-4 was also proposed to play a role in neuronal outgrowth and developmental/pathological angiogenesis via interactions with netrin-1 receptors. Here, we present the high-resolution structure of netrin-4, which shows unique features in comparison with netrin-1, and show that it does not bind directly to any of the known netrin-1 receptors. We show that netrin-4 disrupts laminin networks and basement membranes (BMs) through high-affinity binding to the laminin γ1 chain. We hypothesize that this laminin-related function is essential for the previously described effects on axon growth promotion and angiogenesis. Our study unveils netrin-4 as a non-enzymatic extracellular matrix protein actively disrupting pre-existing BMs.
Highlights
Netrins, a family of laminin-related molecules, have been proposed to act as guidance cues either during nervous system development or the establishment of the vascular system
Together with the fact that most in vitro effects shown with Net[4] were obtained from culture in reconstituted matrix such as Matrigel mainly composed of laminin 111, we hypothesized that the Net[4] by interacting with laminin g1 could impact on the Matrigel in vitro and on the basement membrane (BM) in vivo
We propose that the anti-angiogenic property of Net[4] in vivo is directly related to its impact on BM rearrangement
Summary
A family of laminin-related molecules, have been proposed to act as guidance cues either during nervous system development or the establishment of the vascular system. This was clearly demonstrated for netrin-1 via its interaction with the receptors DCC and UNC5s. We show that netrin-4 disrupts laminin networks and basement membranes (BMs) through high-affinity binding to the laminin g1 chain We hypothesize that this laminin-related function is essential for the previously described effects on axon growth promotion and angiogenesis. On the basis of this high-resolution structure, we designed Net[4] mutants that negatively impede interaction with laminin g1, possibly explaining previously observed ex vivo effects, on axon outgrowth modulation, and angiogenic activity. We propose that the anti-angiogenic property of Net[4] in vivo is directly related to its impact on BM rearrangement
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