Paul Forscher, Ph.D.
I did my PhD thesis work in the Neuroscience Graduate Program at UNC Chapel Hill from 1979-1985. In Dr. Gerry Oxford’s lab I received training in classical excitable membrane biophysics and used the then emergent technology of “patch clamping” to investigate the mechanism of voltage dependent Calcium channel modulation by biogenic amines in dorsal root ganglion (sensory) neurons.
In 1985, I joined Dr. Stephen Smith’s lab in the Section of Molecular Neurobiology and HHMI at Yale University for post doctoral work. I maintained a keen interest in Calcium as a signaling molecule and was hoping to gain some experience in Calcium imaging to compliment my electrophysiological studies; however, by a quirk of scientific fate I began investigating neuronal growth cone motility using high resolution video enhanced DIC microscopy. This unexpected turn of events led me directly into the study of cell motility –a descriptive field of research at the time, especially when compared to the quantitative nature of ion channel biophysics to which I was accustomed. Working in cell motility necessitated learning about cytoskeletal protein dynamics and function, thus, I embarked on the road to becoming a cell biologist.
In 1989 I started my own lab in the Department of Biology (now the Department of Molecular, Cellular, and Developmental Biology) at Yale University. Our research initially focused on characterizing the cytoskeletal protein dynamics and molecular motor activity underlying growth cone motility. Over the years I have maintained an interest in understanding how classical signal transduction pathways (Ca, PKC, PKA, etc.) modulate the cytoskeletal machinery involved in axon growth and guidance.
To investigate mechanisms of growth cone guidance, we developed an in vitro turning assay using silica bead substrates coated with attractive cell adhesion molecules. These bioassays were first used to identify signal transduction pathways involved in substrate dependent growth cone turning and to characterize the role traction forces play in axon advance. A role for src family tyrosine kinases as a mechano-transduction sensor involved in axon guidance emerged from this work.
Recently we have been developing biophysical methods for measuring traction forces that growth cones exert on the underlying substrate while co-assessing cytoskeletal dynamics with fluorescently tagged proteins. These studies yield quantitative data sets amenable to mathematical modeling of the fundamental processes underlying neuronal growth. The long term goal is that these studies will guide therapeutic strategies for treating neurodegenerative disease and our fundamental understanding of axon guidance.