Project Summary/Abstract
How neurons guide their processes to the correct binding partner is a complicated task, but is critical during
development and recovery from injury. It involves the highly coordinated action of many cytoskeletal proteins
and their binding partners within the growth cone at the tips of extending neurites, as they feel their way through
the neuropil. There is a lot known about the signaling pathways that regulate neurite outgrowth and turning, but
the details of how molecular structures come together to achieve growth cone behavior are still unclear. This
project will initially focus on the structure of bundled cofilactin filaments (cofilin-decorated F-actin) in situ, and
how this novel filament structure and fascin cross-linking determine filopodial dynamics. Here we propose that
filopodial behavior is governed partially by the transition from the fascin cross-linked to a cofilin cross-linked
filaments, that makes filopodial bundles more pliable. Experiments are focused around three aims: 1) to study
the high-resolution structure of fascin- and cofilin-linked actin bundles to determine their impact on actin
structure, 2) to determine how changes in fascin and cofilin concentration regulate filopodial dynamics and
structure, and 3) determine how LIMKI and SSH1 form the core of a bidirectional regulatory mechanism for
regulating actin architecture via tuning the phosphorylation state of Ser3 on cofilin.
