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

Temporally dynamic antagonism between transcription and chromatin compaction controls stochastic photoreceptor specification in flies

International audienceStochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). We investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. The ss locus is in a compact state in undifferentiated cells. An early enhancer drives transcription in all R7 precursors, and the locus opens. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In SsON R7s, ss is open and competent for activation by a late enhancer, whereas in SsOFF R7s, ss is compact, and repression prevents expression. Our results suggest that a temporally dynamic antagonism, in which transcription drives large-scale decompaction and then compaction represses transcription, controls stochastic fate specification