The Intracellular Domain of the Frazzled/Dcc Receptor is a Transcription Factor Required for Commissural Axon Guidance

During embryonic development, conserved families of attractive and repulsive cues steer axons by signaling through receptors that are expressed on axonal growth cones. In the canonical model of axon guidance receptor signaling, ligand binding induces the formation of protein complexes on receptor cytoplasmic domains, which locally remodel the growth cone plasma membrane and underlying cytoskeleton. Many axons navigate to their final synaptic targets by passing through a series of intermediate targets, at which they switch their responsiveness to one or more guidance cues. My thesis research identified a new mechanism of axon guidance receptor signaling: the intracellular domain (ICD) of Frazzled (Fra), the Drosophila ortholog of the conserved guidance receptor Deleted in Colorectal Cancer (DCC), functions as a transcription factor to control axon responsiveness to the embryonic ventral midline. In Chapter 1, I introduce the embryonic ventral midline as a model system for studying how axons modulate their responsiveness to guidance cues at intermediate targets and I discuss mechanisms through which DCC transduces signals from its Netrin ligands into local membrane and cytoskeletal rearrangements. In Chapter 2, I present data supporting the idea that the Fra ICD functions as a transcription factor to regulate axonal responsiveness to Slit-Robo repulsion at the midline of the Drosophila embryo. In Chapter 3, I discuss questions that remain regarding the mechanism through which Fra functions as a transcription factor and I examine the implications of this work, focusing on the possibilities that Fra regulates other transcriptional targets and that other axon guidance receptors function as transcription factors.