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Michael B. O'Connor, Ph.D. Professor, Department of Genetics, Cell Biology and Development Associate Investigator, Howard Hughes Medical Institute Ordway Professor of Developmental biology E-mail: moconnor@umn.edu O'Connor Lab Web Site

Research Interests:

During the development of all animals, tissues must grow in a coordinated manner in order to function properly as integrated units within the adult. This is especially important during neuronal wiring. In the case of motoneurons, axons must project over large distances, find a specific target muscle and then maintain appropriate synaptic efficacy during subsequent growth. The latter issue is particularly important during Drosophila neuromuscular development since the muscle volume increases up to 100 fold during larval growth. An inability to coordinate synapse growth with this rapid increase in muscle volume would likely lead to severe impairment of motor control. Remarkably, we have found that BMP signaling regulates the growth and function of the synapse at the Drosophila neuromuscular junction (NMJ). This discovery came from studying the phenotype of mutations in the wishful thinking (wit) gene, a Drosophila homolog of the vertebrate BMP type II receptor. Mutations in wit lead to pharate lethality as a result of an inability of adult animals to escape from the pupal case. We showed that this phenotype is caused by reduced growth of motoneuron synapses at the NMJ and severe defects in neurotransmission. While these results revealed a novel role for BMP signaling in regulating Drosophila NMJ synapse growth and activity, they did not address the source of the signal that stimulates this pathway. More recently, we have collaborated with the Goodman group at UC Berkley to show that Gbb, a BMP 5/6/7 homolog, signals in a retrograde manner (from the muscle to the neuron) to regulate synaptic size and function at the Drosophila NMJ. Like mutations in wit, larvae mutant for gbb exhibit small synapses, reduced neurotransmission and defects in the ultrastructure of synaptic active zones. However, unlike Wit, which is specifically required in the presynaptic (neuronal) cell, we showed that restoring gbb expression in muscles, partially rescues the gbb synaptic defects. These results reveal that target -derived BMP signals are required to properly coordinate muscle and synapse growth at the Drosophila NMJ.

Interestingly, we have also recently discovered that Gbb signaling through Wit influences the expression of circulating neuropeptides known as FMRFs. These peptides modulate the physiological properties of the NMJ. These observations have lead us to suggest that BMP signaling provides not only a local cue that regulates the growth of the NMJ synapses, but also a global cue that controls systemic modulation of NMJ activity by the neuroendocrine system.

Selected Publications:

Ting CY, Herman T, Yonekura S, Gao S, Wang J, Serpe M, O'Connor MB, Zipursky SL, Lee CH. Tiling of r7 axons in the Drosophila visual system is mediated both by transduction of an activin signal to the nucleus and by mutual repulsion. Neuron. 2007 Dec 6;56(5):793-806.

McBrayer Z, Ono H, Shimell M, Parvy JP, Beckstead RB, Warren JT, Thummel CS, Dauphin-Villemant C, Gilbert LI, O'Connor MB. Prothoracicotropic hormone regulates developmental timing and body size in Drosophila. Dev Cell. 2007 Dec;13(6):857-71.

Rewitz KF, O'Connor MB, Gilbert LI. Molecular evolution of the insect Halloween family of cytochrome P450s: phylogeny, gene organization and functional conservation. Insect Biochem Mol Biol. 2007 Aug;37(8):741-53. Epub 2007 Mar 5.

Sun M, Thomas MJ, Herder R, Bofenkamp ML, Selleck SB, O'Connor MB. Presynaptic contributions of chordin to hippocampal plasticity and spatial learning. J Neurosci. 2007 Jul 18;27(29):7740-50.

Knox S, Ge H, Dimitroff BD, Ren Y, Howe KA, Arsham AM, Easterday MC, Neufeld TP, O'Connor MB, Selleck SB. Mechanisms of TSC-mediated control of synapse assembly and axon guidance. PLoS ONE. 2007 Apr 18;2(4):e375.

Umulis D, O'Connor MB, Othmer HG. 2 Robustness of Embryonic Spatial Patterning in Drosophila melanogaster. Curr Top Dev Biol. 2007;81:65-111.

Serpe M, O'Connor MB. The metalloprotease tolloid-related and its TGF-beta-like substrate Dawdle regulate Drosophila motoneuron axon guidance. Development. 2006 Dec;133(24):4969-79.

Takaesu NT, Hyman-Walsh C, Ye Y, Wisotzkey RG, Stinchfield MJ, O'connor MB, Wotton D, Newfeld SJ. dSno facilitates baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2. Genetics. 2006 Nov;174(3):1299-313.

Ono H, Rewitz KF, Shinoda T, Itoyama K, Petryk A, Rybczynski R, Jarcho M, Warren JT, Marques G, Shimell MJ, Gilbert LI, O'Connor MB. Spook and Spookier code for stage-specific components of the ecdysone biosynthetic pathway in Diptera. Dev Biol. 2006 Oct 15;298(2):555-70.

Umulis DM, Serpe M, O'Connor MB, Othmer HG.   Robust, bistable patterning of the dorsal surface of the Drosophila embryo. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11613-8.

Jadrich JL, O'Connor MB, Coucouvanis E. The TGF beta activated kinase TAK1 regulates vascular development in vivo. Development. 2006 Apr;133(8):1529-41.

O'Connor MB, Umulis D, Othmer HG, Blair SS. Shaping BMP morphogen gradients in the Drosophila embryo and pupal wing. Development. 2006 Jan;133(2):183-93. Review.