Molecular Dynamics of Guided Axon Growth
Paul Forscher, Ph.D.

Paul Forscher, Ph.D.

Professor of Molecular, Cellular & Developmental Biology
Room: KBT 222
Phone: (203) 432-6344/6345
Web site

B.A. Colby College, ME 1974; Ph.D. UNC-Chapel Hill 1985

Have you ever wondered how your brain got wired up in the first place? How a single neuron finds a unique signaling partner with over 10 billion other neurons to choose from? During development and nerve regeneration after injury neurons not only face this daunting task, but often have to migrate extremely long distances (>50,000 cell diameter equivalents) to accomplish it! My lab has focused its attention on this problem and the specialized guidance device called the growth cone that provides the motility and signal transduction capabilities needed for axon guidance. Current lab projects are in three related areas

  1. Molecular motor and cytoskeletal protein dynamics underlying growth cone motility.
  2. Cell surface receptors involved in target recognition.
  3. Investigation of signal transduction pathways involved in controlling the cytoskeletal protein effectors involved.

We address the relevant cell biological processes using a "molecular physiology" approach. This typically entails generation of molecular probes which are used to investigate dynamics of the process and/or protein-protein interactions in living neurons. We use a variety of high resolution imaging and biophysical approaches such as: multimode fluorescent speckle TIRF microscopy, laser trapping, photobleaching and "caged" probe photoactivation to achieve these ends.

Electron micrograph of Aplysia neuronal growth cone cytoskeleton with immunofluorescence inset showing the filamentous actin structures (red) and microtubules (green) caught "exploring" the growth cone's leading edge by tracking down an actin bundle that guides microtubule assembly. The underlying molecular dynamics are shown in a living growth cone in the time montage at the right. Time proceeds from top to bottom at 10 seconds per image frame.

Neuronal growth cone target interaction in vitro evoked by a glass bead coated with the homophilic cell adhesion molecule, apCAM. Time montage (right) shows progressive advance of the central cytoplasmic domain toward the target interaction site (time is down). This results from directed extension of microtubules toward the bead target (bottom left; microtubules (green) and actin filaments (red).

Selected Publications

Zhang, X. F., Schaefer, A. W., Burnette, D. T., Schoonderwoert, V. T., and Forscher, P. (2003). Rho-dependent contractile responses in the neuronal growth cone are independent of classical peripheral retrograde actin flow. Neuron 40, 931-944.

Schaefer, A. W., Kabir, N., and Forscher, P. (2002). Filopodia and actin arcs guide the assembly and transport of two populations of microtubules with unique dynamic parameters in neuronal growth cones. J Cell Biol 158, 139-152.

Suter, D. M., and Forscher, P. (2001). Transmission of growth cone traction force through apCAM-cytoskeletal linkages is regulated by Src family tyrosine kinase activity. J Cell Biol 22, 22.

Figure 3
Microtubule dynamics promote efficient exploration of the peripheral cytoplasmic domain of a neuronal growth cone. An example of a single dynamically unstable microtubule undergoing assembly followed by disassembly (bottom). Microtubule behavior integrated over 10 minutes in the peripheral growth cone lamellipodium (top).

Laser Trapping
An infrared laser "tweezers" is being used to beam small (100 nm diameter) ligand coated glass beads down to the cell surface to explore receptor protein dynamics. Note that this bead moves linearly over time in the montage below (each frame = 5 seconds) due to receptor interactions with the underlying moving actin cytoskeleton.



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