Adhesion Signaling and Mechanotransduction in Axon Guidance

Extensive research has shown that chemical ligands activate cell surface receptors on growth cones leading to intracellular signals that direct cytoskeletal changes. However, the environment also provides mechanical support for growth cone adhesion and traction forces that stabilize leading edge protrusions. Interestingly, recent work suggests that both the mechanical properties of the environment and mechanical forces generated within growth cones influence axon guidance. We are examining the molecular mechanisms involved in growth cone force production and detection and are testing how these processes may be necessary for the development of proper neuronal circuits.


Current Open Questions:

  1. How do chemical axon guidance cues influence integrin adhesion dynamics?
  2. How do clutching forces of point contact adhesions regulate F-actin retrograde flow and does this control axon pathfinding in vivo?
  3. What proteins function as menchanosensors on growth cones and how are molecular forces transferred onto target proteins?
  4. What mechanosensitive (MS) ion channels are expressed on growth cones and how are MS ion channels gated at the plasma membrane?
  5. What are the down stream targets of calcium influx through specific ion channels how does calcium effector activation regulate growth cone motility?
  6. What are the roles for differential tissue elasticity and mechanical signaling in neuronal morphogenesis in vivo?


Force generation and force sensing in neuronal growth cones. A neuronal growth cone is labeled for filamentous actin (red) and bI-II tubulin (green) using immunocytochemistry. This super resolution image was captured using structure illumination microscopy as previously described (Santiago-Medina et al., 2015). Overlaying the image are schematic elements depicting myosin dimers (purple) and adhesion complexes (yellow) near the central and peripheral growth cone, respectively. Myosin bound to actin produces a rearward force (purple arrows) on adhesion complexes where mechanosensitive (MS) proteins (parallel springs) detect this force. Adhesion complexes antagonize this rearward force allowing actin polymerization to expand the leading edge membrane (yellow arrows) and stretching a set of membrane MS proteins (perpendicular springs). Figure published in: Kerstein et al., Frontiers in Neuroscience, 2015. Below is a time-lapse movie of a living growth cone expressing GFP-dSH2, which labels areas containing tyrosine phosphorylated proteins (eg point contact adhesions) and is additionally labeled with TMR-KaberimideC to track F-actin retrograde flow.