Abstract
Dynamic mechanical interactions between adhesion complexes and the cytoskeleton are essential for axon outgrowth and guidance. Whether planar cell polarity (PCP) proteins, which regulate cytoskeleton dynamics and appear necessary for some axon guidance, also mediate interactions with membrane adhesion is still unclear. Here we show that Vangl2 controls growth cone velocity by regulating the internal retrograde actin flow in an N-cadherin-dependent fashion. Single molecule tracking experiments show that the loss of Vangl2 decreased fast-diffusing N-cadherin membrane molecules and increased confined N-cadherin trajectories. Using optically manipulated N-cadherin-coated microspheres, we correlated this behavior to a stronger mechanical coupling of N-cadherin with the actin cytoskeleton. Lastly, we show that the spatial distribution of Vangl2 within the growth cone is selectively affected by an N-cadherin-coated substrate. Altogether, our data show that Vangl2 acts as a negative regulator of axonal outgrowth by regulating the strength of the molecular clutch between N-cadherin and the actin cytoskeleton.
Highlights
Core planar cell polarity (PCP) is a conserved signaling pathway known to regulate cytoskeleton dynamics in a large variety of cell types
Our study shows that the absence of Vangl2 in young neurons increases the migration rate of the neuronal growth cone, due to a reduced turnover of N-cadherin adhesions resulting in an increased mechanical connection to the actin retrograde flow
These observations support a model in which endogenous Vangl2 acts as a negative regulator of a molecular clutch between N-cadherin adhesions and F-actin in growth cones (Model, Figure 9)
Summary
Core planar cell polarity (PCP) is a conserved signaling pathway known to regulate cytoskeleton dynamics in a large variety of cell types. Careful analysis of the brains of Fzd and Celsr singlemutant mice revealed strikingly similar defects in axonal tract formation, such as in the anterior commissure and the thalamocortical and corticothalamic tracts (Tissir et al, 2005; Tissir and Goffinet, 2013; Wang et al, 2006; Zhou et al, 2008) Both genes are required for the guidance of monoaminergic axons along the anterior-posterior axis and in the anterior turning of commissural axons in the spinal cord (Fenstermaker et al, 2010; Lyuksyutova et al, 2003). Our study highlights a novel molecular function of Vangl in early hippocampal development and defines Vangl as a neuronal molecular brake in young neurons
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