Kate O'Connor-Giles

Research Description:
Proper regulation of synaptic development and plasticity are fundamental to the function of neural circuits. Defects in synaptic growth are associated with a broad range of neurological disorders. However, the molecular mechanisms regulating synaptic growth are not well understood. Our research employs the Drosophila neuromuscular junction (NMJ) as a model system for dissecting the intrinsic and trans-synaptic mechanisms through which neurons and their targets coordinate the assembly and growth of synapses. We are currently focusing on:

1. Identification and characterization of novel regulators of synapse formation and function. The identification and characterization of novel regulators of synapse formation and function can expand our understanding of this intricate process in unexpected ways. To that end, we have conducted forward genetic screens for genes required for proper synapse development. We are now employing genetic, imaging, biochemical, electrophysiological and behavioral approaches to characterize the regulators we have identified.

One such gene is Fife, the Drosophila homolog of Piccolo, a core component of presynaptic active zones previously believed absent from invertebrate proteomes. We have found that Fife regulates synaptic architecture at active zones to control neurotransmitter release. We are currently working to understand the molecular mechanisms of Fife function and its role in synaptic plasticity.

2. Trans-synaptic regulation of growth factor signaling. It is well known that postsynaptic cells can regulate the size and strength of the synaptic inputs they receive through instructive signaling to presynaptic neurons. We have found that presynaptic neurons, rather than passive recipients of these cues, can control their level of responsiveness to signals from their postsynaptic partners through the endocytic regulation of growth factor receptors. We are studying the role of this mechanism in synapse development and plasticity.

3. Genome engineering. Genetic and molecular techniques to manipulate the genomes of organisms are invaluable tools for understanding gene function. In collaboration with the Wildonger and Harrison labs, we have recently shown that in Drosophila the bacterially derived CRISPR RNA-guided Cas9 nuclease can be employed to generate defined deletions and gene replacement by homologous recombination, and that these genome modifications can be transmitted through the germline. The ease of producing chiRNAs to guide sequence-specific targeting makes the CRISPR RNA/Cas9 system an appealingly simple method for genome editing. From the initial cloning steps to identification of transformants, stable lines with targeted genome alterations can be generated within a month. For more information visit the flyCRISPR website and discussion board.

Representative Publications:
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Gratz, S.J., Wildonger, J., Harrison, M.M., and O’Connor-Giles, K.M. (2013). CRISPR Methods and Protocols: Genome editing in Drosophila. Methods in Molecular Biology. In progress (invited chapter).

Gratz, S.J., Wildonger, J., Harrison, M.M., and O’Connor-Giles, K.M. (2013). CRISPR/Cas9-mediated genome engineering and the promise of designer flies on demand. Fly. Submitted (invited review).

Gratz, S.J., Cummings, A.M., Nguyen, J.N., Hamm, D.C., Donohue, L.K., Harrison, M.M., Wildonger, J., and O’Connor-Giles, K.M. (2013). Genome Engineering of Drosophila with the CRISPR RNA-Guided Cas9 Nuclease. GENETICS. 194(4), 1029-1035

Bruckner, J*., Gratz, S*., Slind, J., Geske, R., Cummings, A., Galindo, S., Donohue, L. and O’Connor-Giles, K. (2012) Fife, a Drosophila Piccolo-RIM homolog, promotes active zone organization and neurotransmitter release. J Neuorsci. 32(48), 17048-58.

*These authors contributed equally.

Babaoglan, A.B., O’Connor-Giles, K.M., Mistry, H. Schickedanz, A., Wilson, B.A. and Skeath, J.B. (2009). Sanpodo: a context-dependent activator and inhibitor of Notch signaling during asymmetric divisions. Development 136, 4089-4098.

O’Connor-Giles, K.M. and Ganetzky, B. (2008). Satellite Signaling at Synapses. Fly 2(5), 259-261.

O’Connor-Giles, K.M., Ho, L.L. and Ganetzky, B. (2008). Nervous wreck interacts with Thickveins and the endocytic machinery to attenuate retrograde BMP growth signaling during synaptic growth. Neuron 58, 507-518.

Eberl, D., Kitamoto, T., Berke, B., O’Connor-Giles, K., Ueda, A., Lee, J., Ruan, H., Engel, J. and Ganetzky, B. (2008). Meeting report: genes, neurons, circuits, and behaviors: highlights of Cold Spring Harbor Meeting on Drosophila neurobiology. Oct 3-7, 2007. Journal of Neurogenetics 22, 3-13.

O’Connor-Giles, K.M. and Skeath, J.B. (2003) Numb inhibits membrane localization of Sanpodo, a four-pass transmembrane protein, to promote asymmetric divisions in Drosophila. Dev Cell 5(2), 231-43.