How axons in the developing nervous system successfully navigate to their correct targets is a fundamental problem in neurobiology. Axons are guided by both attractive and repulsive cues, which are members of evolutionary conserved protein families. We propose to study the signaling mechanisms that function during repulsive axon guidance. The midline of the Drosophila embryonic central nervous system (CNS) provides an ideal system to address these questions. Like its structural analog, the vertebrate floor plate, the fly midline is an intermediate target for many classes of navigating axons, which must decide whether or not to cross. In the Drosophila CNS, the conserved guidance cue Slit and its neuronal receptors the Roundabouts (Robo), play multiple roles in patterning axonal connections at the midline, acting primarily as axonal repellants. The primary aims of this proposal are to 1) test the hypothesis that proteolytic processing directly contributes to Robo repulsion and to signal termination, 2) to investigate how the identified Robo signaling components Abelson, Son of Sevenless and CrossGAP function together to coordinate signaling downstream of Robo and 3) to dissect the mechanisms underlying the distinct repulsive functions of the three Drosophila Robo family members. We have established genetic and direct biochemical links between a specific metalloprotease and regulation of Robo repulsion and have the necessary genetic, biochemical and cell biological assays to investigate the mechanism by which proteolytic processing influences repulsion. Similar kinds of approaches well established in our laboratory will allow for our continued investigation of how signaling molecules that function downstream of Robo coordinately regulate axon repulsion. A previously successful chimeric receptor approach where different portions of the Robo1, Robo2 and Robo3 receptors are exchanged with each other and then assayed for function in transgenic flies will be used to understand how different Robo receptors lead to distinct repulsive events. Together these studies promise to enrich our understanding of Slit-Robo signaling during normal development and may provide new therapeutic targets for diverse human health problems, ranging from developmental disorders of the nervous system to spinal cord injury and stroke.
The proposed research has the potential to make important contributions to the understanding of developmental disorders of the nervous system, regeneration after injury and in addition may provide insight into malignancy in various kinds of cancer. The Slit-Roundabout signaling system has a well-established role in regulating wiring in the nervous system, suggesting that understanding Slit-Robo signaling during normal development may provide new targets for therapies for diverse human health problems, ranging from stroke and spinal cord injury to developmental disorders of the nervous system and neurodegenerative disease.
|Chance, Rebecca K; Bashaw, Greg J (2015) Slit-Dependent Endocytic Trafficking of the Robo Receptor Is Required for Son of Sevenless Recruitment and Midline Axon Repulsion. PLoS Genet 11:e1005402|
|Neuhaus-Follini, Alexandra; Bashaw, Greg J (2015) The Intracellular Domain of the Frazzled/DCC Receptor Is a Transcription Factor Required for Commissural Axon Guidance. Neuron 87:751-63|
|Evans, Timothy A; Santiago, Celine; Arbeille, Elise et al. (2015) Robo2 acts in trans to inhibit Slit-Robo1 repulsion in pre-crossing commissural axons. Elife 4:e08407|
|Neuhaus-Follini, Alexandra; Bashaw, Greg J (2015) Crossing the embryonic midline: molecular mechanisms regulating axon responsiveness at an intermediate target. Wiley Interdiscip Rev Dev Biol 4:377-89|
|Santiago, Celine; Labrador, Juan-Pablo; Bashaw, Greg J (2014) The homeodomain transcription factor Hb9 controls axon guidance in Drosophila through the regulation of Robo receptors. Cell Rep 7:153-65|
|O'Donnell, Michael P; Bashaw, Greg J (2013) Distinct functional domains of the Abelson tyrosine kinase control axon guidance responses to Netrin and Slit to regulate the assembly of neural circuits. Development 140:2724-33|
|O'Donnell, Michael P; Bashaw, Greg J (2013) Src inhibits midline axon crossing independent of Frazzled/Deleted in Colorectal Carcinoma (DCC) receptor tyrosine phosphorylation. J Neurosci 33:305-14|
|Evans, Timothy A; Bashaw, Greg J (2012) Slit/Robo-mediated axon guidance in Tribolium and Drosophila: divergent genetic programs build insect nervous systems. Dev Biol 363:266-78|
|Coleman, Hope A; Labrador, Juan-Pablo; Chance, Rebecca K et al. (2010) The Adam family metalloprotease Kuzbanian regulates the cleavage of the roundabout receptor to control axon repulsion at the midline. Development 137:2417-26|
|Evans, Timothy A; Bashaw, Greg J (2010) Functional diversity of Robo receptor immunoglobulin domains promotes distinct axon guidance decisions. Curr Biol 20:567-72|
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