A molecular clutch between the actin flow and N-cadherin adhesions drives growth cone migration.
The adhesion molecule N-cadherin plays important roles in the development of the nervous system, in particular by stimulating axon outgrowth, but the molecular mechanisms underlying this effect are mostly unknown. One possibility, the so-called "molecular clutch" model, could involve a direct mechanical linkage between N-cadherin adhesion at the membrane and intracellular actin-based motility within neuronal growth cones. Using live imaging of primary rat hippocampal neurons plated on N-cadherin-coated substrates and optical trapping of N-cadherin-coated microspheres, we demonstrate here a strong correlation between growth cone velocity and the mechanical coupling between ligand-bound N-cadherin receptors and the retrograde actin flow. This relationship holds by varying ligand density and expressing mutated N-cadherin receptors or small interfering RNAs to perturb binding to catenins. By restraining microsphere motion using optical tweezers or a microneedle, we further show slippage of cadherin-cytoskeleton bonds at low forces, and, at higher forces, local actin accumulation, which strengthens nascent N-cadherin contacts. Together, these data support a direct transmission of actin-based traction forces to N-cadherin adhesions, through catenin partners, driving growth cone advance and neurite extension.
Unité Mixte de Recherche 5091, Centre National de la Recherche Scientifique, Institut Francois Magendie, Université Bordeaux 2, 33077 Bordeaux, France.
Lucie
L
Bard
Cécile
C
Boscher
Mireille
M
Lambert
René-Marc
RM
Mège
Daniel
D
Choquet
Olivier
O
Thoumine
D000199:Actins / Q000502:physiology*; D000818:Animals; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002645:Chickens; D020439:Growth Cones / Q000502:physiology* / Q000648:ultrastructure; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000000981:diagnostic imaging / Q000502:physiology; D011859:Radiography; D051381:Rats; D014981:Xenopus
D000199:Actins; D015820:Cadherins