|Assistant Research Professor|
|145 Bevier Rd. Piscataway, NJ 08854|
We use a combination of molecular genetics, cell biology, and electrophysiology in the nematode Caenorhabditis elegans to answer important questions in neuroscience.
A plethora of post-translational modifications can be reversibly added to microtubules. These post-translational modifications in combination are proposed to act as a “Tubulin Code” that regulates microtubule stability and motor traffic. We study how glutamylation, or addition of glutamate side-chains, to microtubules regulates their function as part of the Tubulin Code.
The deglutamylase CCPP-1 is a key regulator of cytoskeletal stability and motor traffic in sensory neuronal cilia. We found that, consistent with the Tubulin Code hypothesis, loss of the deglutamylase CCPP-1 causes dramatic cytoskeletal instability in a subset of sensory neurons and abnormally fast kinesin-2 motility in another subset. In mammals, the CCPP-1 homolog is implicated in both neurodegeneration and regeneration after injury, highlighting the importance of the Tubulin Code.
We conducted a forward genetic screen for mutations that suppress the microtubule instability defect of ccpp-1 mutants and have isolated fifteen independent mutations. We hope that my ccpp-1 suppressors will identify novel molecular targets for treatment of neurodegeneration or spinal cord injury in humans.
O'Hagan, R., Silva, M., Bellotti, S., and Barr, M. M. The Glutamylase TTLL-11 Regulates Ciliary Microtubule Structure, Polycystin Trafficking, and Extracellular Vesicle Release in C. elegans Sensory Neurons. (Manuscript in Preparation)
Chen, Y, Bharill, S, Altun, Z, O'Hagan, R, Coblitz, B, Isacoff, EY, Chalfie, M.
Lockhead, D., Schwarz, E. M., O’Hagan, R, Bellotti, S., Krieg, M., Barr, M. M., Dunn, A. R., Sternberg, P. W., and Goodman, M. B. The tubulin repertoire of Caenorhabditis elegans sensory neurons and its context?dependent role in process outgrowth. Mol. Biol. Cell 27:23 3717-3728, (2016)
O'Hagan, R. and Barr, M. M. A motor relay on ciliary tracks. An invited “News & Views” commentary in Nat Cell Biol. Nov 27;17(12):1517-1519 (2015)
Chen, Y., Bharill, S., O’Hagan, R., Isacoff, E. Y., and Chalfie, M. MEC-10 and MEC-19 reduce the neurotoxicity of the MEC-4(d) DEG/ENaC channel in Caenorhabditis elegans. G3: Genes, Genomes, Genetics April 1, (6): 41121-1130 (2016)
O'Hagan, R., Wang, J. and Barr, M. M. Mating Behavior, Male Sensory Cilia, and Polycystins in C. elegans. An Invited Review in Semin Cell Dev Biol. Sept; 33C:25-33 (2014)
O'Hagan, R., and Barr, M. M. Regulation of Tubulin Deglutamylation Plays Cell-Specific Roles in the Function and Stability of Sensory Cilia. Worm July/Aug/Sept; 1 (3):155-159 (2012)
O'Hagan, R., Piasecki, B. P., Silva, M., Phirke, P., Nguyen, C. Q., Hall, D. H., Swoboda, P. and Barr, M. M. The Tubulin Deglutamylase CCPP-1 Regulates the Function and Stability of Sensory Cilia in C. elegans. Curr Biol. Oct. 25; 21 (20): 1685-1694 (2011)
Árnadóttir, J., O'Hagan, R., Chen, Y., Goodman, M.B., and Chalfie, M. The DEG/ENaC protein MEC-10 regulates the transduction channel complex in Caenorhabditis elegans touch receptor neurons. J Neurosci. Aug 31; 31 (35):12695-12704 (2011)
Vansteenhouse, H.C., Horton, Z.A., O'Hagan, R., Tai, M.H., Zipser, B. Phylogenetic conservation of the cell-type-specific Lan3-2 glycoepitope in Caenorhabditis elegans. Dev Genes Evol. Sep; 220 (3-4): 77-87 (2010)
Bounoutas, A, O'Hagan, R., Chalfie, M. The multipurpose 15-protofilament microtubules in C. elegans have specific roles in mechanosensation. Curr Biol. Aug 25; 19 (16): 1362-1367 (2009)
O’Hagan, R. and Chalfie, M. “Mechanosensation In C. elegans.” A chapter in a thematic volume from Elsevier Press entitled The Neurobiology of C. elegans, Vol. 69 (2006), edited by Eric Aamodt and Cindy Minor.
O’Hagan, R., Chalfie, M., and Goodman, M.B. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans touch receptor neurons transduces mechanical signals. Nat Neurosci. 8 (1), 43-50 (2005)
Tobias, M.L., Bernard, C., O’Hagan, R., Horng, S., Rand, M., and Kelley, D. B. Vocal communication between male Xenopus laevis. Animal Behaviour, 67, Issue 2, 353-365 (2004)
Goodman, M.B., Ernstrom, G., Chelur, D.S., O’Hagan, R., Yao, C., and Chalfie, M. MEC-2 regulates C. elegans DEG/ENaC channels needed for mechanosensation. Nature 415, 1039-1042 (2002)
Chelur, D.S., Ernstrom, G., Goodman, M.B., Yao, C., Chen, L., O’Hagan, R. and Chalfie, M. The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel. Nature 420, 669-673 (2002)