Principal Investigator Frank Gertler
Another form of actin-based motility that we study involves neuronal growth cone migration in response to guidance cues. Growth cone movement is dominated by filopodia, structures formed by parallel bundles of actin filaments. The lamellipodial veil in between growth cone filopodia is usually concave, unlike the convex shape of fibroblast lamellipodia. The concave shape suggests that growth cone “lamellipodia” may not be a protrusive structure in the traditional sense, but may be dragged along by the motile forces of filopodia. In contrast to the highly branched arrays within fibroblast lamellipodia, the actin network in growth cones is dominated by thick parallel bundles of filaments that comprise filopodia with a less dense network of relatively long filaments and a comparatively low density of branched networks near the edge of the lamellipodial veil. We hypothesize that growth cones and fibroblasts utilize different balances of actin modifying proteins and structures during movement and guidance and are testing this hypothesis by a variety of approaches.
Recently, we generated mutant mouse embryos that lack all three Ena/VASP proteins. Triple mutants survive until late embryogenesis and exhibit a number of interesting phenotypes. Mutant cortices exhibit an almost complete loss of axonal fibers. Interestingly, some neurons migrate beyond the outer layer of the cortex to form ectopic clusters. Such ectopia form axons as do other types of neurons in the mutants including retinal neurons and neurons that form spinal nerves. At a cellular level, loss of Ena/VASP results in almost complete absence of filopodia on neurons. We hypothesize that filopodia serve to guide and stabilize microtubules at the cell periphery and that microtubule invasion is a key step in axonogenesis. We are using the triple mutant animals to study axonogenesis and to explore the function of Ena/VASP in response to axon guidance cues.