My lab is currently working on three main projects:
(1) Intracellular signaling during neurite outgrowth and sprouting. The aim of this research is to identify the intracellular signaling mechanisms important for neuronal outgrowth and to determine their effect on the cytoskeletal network. Recently we have shown that axon consolidation is an active process and that neurite sprouting is suppressed along the length of a neurite. We are currently examining the regulation of this signaling mechanism and identifying approaches to inhibit the signaling and stimulate neurite sprouting. In addition, we are also examining how the cytoskeleton changes in a neuron as it grows in its normal embryonic environment. Using a model insect system of neuronal growth, we analyze the location and activity of key regulators of cytoskeleton function in order to assess how neurons grow and turn in response to embryonic guidance cues. Using sophisticated imaging technologies we will provide some of the first observations of cytoskeletal dynamics of growing neurons in their embryonic environment.
(2) Identification of small molecules that stimulate neurite outgrowth and regeneration. We have recently established a high throughput screen to identify novel compounds that will stimulate neuronal growth and regeneration on inhibitory substrates. Our goal for this project is to test these molecules in animal models as potential ther apeutics to stimulate neuronal regeneration and sprouting in the injured spinal cord. In the future we hope to similarly examine whether these molecules can provide therapeutic benefits to neurodegenerative disease models.
(3) Examination of the role of semaphorins during embryonic development. The aim of this project is to determine the function of semaphorins in the developing nervous system. Semaphorins are the largest class of guidance cue that is expressed in the developing nervous system and many of these molecules have been shown to repel or inhibit neurons as they grow. We are particularly interested in the biochemical regulation of semaphorin function and the receptors and second messenger systems that are stimulated by semaphorins. In addition, we are interested in examining the dynamic distribution of semaphorins, particularly with respect to the distribution of the functional regions of the semaphorin protein. Presently we are working on Semaphorins 1, 2 and 5.
Lise M-F, Strivastava D, Arstikaitis P, Lett R, Sheta R, Viswanathan V, Penzes P, TP O’Connor and A El-Husseini (2009) Novel Myosin Va interacting protein, RILPL2, controls cell shape and neuronal morphogenesis via Rac signaling. J Cell Science 15:3870-21.
TP O’Connor, Cockburn K, Wang W, Tapia L, Currie E, Bamji SX (2009) Semaphorin 5B mediates synapse elimination in hippocampal neurons. Neural Development, 4:18.
Lett RL, Wang W, TP O’Connor (2009) Semaphorin 5B is a novel inhibitory cue for corticofugal axons. Cerebral Cortex (6):1408-21.
Mingorance-Le Meur A, Mohebiany AN, TP O’Connor (2009) Varicones and growth cones: two neurite terminals in PC12 cells. PLoS One 4(2):e4334.
Mingorance-Le Meur A, TP O’Connor (2008) Neurite consolidation is an active process requiring constant repression of protrusive activity. EMBO Journal 28(3):248-60.
Wong JW, McPhail LT, Brastianos HC, Andersen RJ, Ramer MS, TP O’Connor (2008) A novel diketopiperazine stimulates sprouting of spinally projecting axons. Experimental Neurology 214(2):331-40.
To KC, Church J, TP O’Connor (2008) Growth cone collapse stimulated by both calpain- and Rho-mediated pathways. Neuroscience 153(3):645-53.
Wong JW, Brastianos HC, Andersen RJ, TP O’Connor (2008) A high-throughput screen to identify novel compounds to promote neurite outgrowth. Journal of Neuroscience Methods 169(1):34-42.
To KC, Church J, TP O’Connor (2007) Combined activation of calpain and calcineurin during ligand-induced growth cone collapse. Molecular and Cellular Neuroscience 36(4):425-34.
To KC, Loh KT, Roskelley CD, Andersen RJ, TP O’Connor (2006) The anti-invasive compound motuporamine C is a robust stimulator of neuronal growth cone collapse. Neuroscience 139(4):1263-74.
Isbister CM, MacKenzie PJ, To KCW and TP O’Connor (2003) Gradient steepness influences the pathfinding decisions of neuronal growth cones in vivo. J Neuroscience 23:193-202.
Mills J, Digicaylioglu M, Legg AT, Young CE, Young SS, Young, Barr AM, Fletcher L, TP O’Connor and Dedhar S (2003) Role of integrin-linked kinase in nerve growth factor-stimulated neurite outgrowth. J Neuroscience 23:1638-1648.
Legg AT and TP O’Connor (2003) Gradients and growth cone guidance of grasshopper neurons. Journal of Histochemistry 51:445-454. (Review)
Bonner J, Auld V and TP O’Connor (2002) Migrating mesoderm establish a uniform distribution of laminin in the developing grasshopper embryo. Developmental Biology 249:57-73.
Bonner J and TP O’Connor (2001) The permissive cue laminin is essential for growth cone turning in vivo. J Neuroscience 21:9782-9791.
Bonner J and TP O’Connor (2000) Semaphorin function in the developing invertebrate peripheral nervous system. Biochem and Cell Biol 78:603-611. (Review)
Isbister C and TP O’Connor (2000) Mechanisms of growth cone guidance and motility in the developing grasshopper embryo. J Neurobiology 44:271-280.
Wong JTW, Wong STM and TP O’Connor (1999) Ectopic semaphorin-1a functions as an attractive guidance cue for developing peripheral neurons. Nature Neuroscience 2:798-803.
Isbister C, Tsai A, Wong S, Kolodkin AL and TP O’Connor (1999) Discrete roles for secreted and transmembrane semaphorins in neuronal growth cone guidance in vivo. Development 126:2007-2019.