Brock Grill, Ph.D.
Ph.D., University of British Columbia, Vancouver, BC, Canada, 2003
Department of Neuroscience
The Scripps Research Institute
130 Scripps Way C325
Jupiter, Florida 33458
Formation and wiring of the brain requires that single neurons coordinate and regulate numerous events during development. An individual neuron must extend a single axon, the axon must locate appropriate target cells and form synaptic connections, and the axon's growth must be terminated at the appropriate time and location. Billions of individual neurons have to execute and coordinate these events in time and space to form a human brain. Understanding how even a single neuron performs this feat remains a major goal in neuroscience.
While our understanding has grown significantly in recent years regarding how individual events in a neuron's development are regulated, we know very little about how different events are coordinated and integrated, particularly on a molecular level. The goal of the Grill lab is to identify and analyze candidate molecular coordinators of neuronal development. To this end, we rely upon a simple model system, the nematode Caenorhabditis elegans, for several reasons. 1) The major events in the life of a developing C. elegans neuron, and the known molecular mechanisms that govern these events, are conserved with mammals. 2) Genome-wide genetic and transgenic techniques are well developed in C. elegans, which combined with the animal's short life-cycle allow us to rapidly obtain important functional information about molecules of interest. 3) The Grill lab specializes in using proteomic screens to decipher the composition and function of protein complexes that regulate axon outgrowth and synapse formation.
Once conserved signaling proteins that coordinate different events in neuronal development have been identified, we plan to use targeted drug screens to identify pharmaceuticals that can regulate their activity. It is our hope that such drugs will stimulate new synapse formation and/or axon outgrowth, and be potential therapeutics to treat conditions that cause a loss of synaptic connections, such as neurodegenerative diseases (e.g. Alzheimer's disease) and stroke.
At present, we have growing evidence that the Regulator of Presynaptic Morphology (RPM)-1 is an excellent candidate as a coordinator of different events in neuronal development. RPM-1 regulates synapse formation, axon termination, and axon guidance in C. elegans, Drosophila, and mice. We have established that RPM-1 functions through multiple downstream signaling pathways, including the Dual Leucine zipper-bearing Kinase (DLK)-1. Interestingly, both RPM-1 and DLK-1 also function in axon regeneration in C. elegans and Drosophila suggesting that the developmental mechanisms that control synapse formation and axon outgrowth also regulate axon regeneration. Our emerging data has shown that RPM-1 uses different mechanisms to regulate both short and long-term activity of DLK-1, suggesting that RPM-1 has the ability to fine-tune the activity of DLK-1. At present, we are actively engaged in trying to understand how RPM-1's activity is regulated, and if specific extracellular signals control the activity of RPM-1. We are also interested in determining if RPM-1 functions through further unknown mechanisms to control synapse formation and axon growth.
Opperman KJ, Mulcahy B, Giles AC, Risley MG, Birnbaum RL, Tulgren ED, Dawson-Scully K, Zhen M and Grill B. (2017) The HECT family ubiquitin ligase EEL-1 regulates neuronal function and development. Cell Reports in press.
Baker ST and Grill B. (2017) Defining minimal binding regions in regulator of presynaptic morphology 1 (RPM-1) using C. elegans neurons reveals differential signaling complexes. Journal of Biological Chemistry 292:2519-2530.
Risley MG, Kelly SP, Jia K, Grill B, Dawson-Scully K. (2016) Modulating behavior in C. elegans using electroshock and antiepileptic drugs. PLoS One 11(9):e0163786.
Grill B, Murphey RK, Borgen MA. (2016) The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration. Neural Development 11:8 doi: 10.1186/s13064-016-0063-0.
Giles AC, Opperman KJ, Rankin CH and Grill B. (2015) Developmental function of the PHR protein RPM-1 is required for learning in C. elegans. G3 (Bethesda) 5:2745-2757.
Baker S, Turgeon S, Tulgren E, Wigant J, Rahimi O, Opperman K and Grill B. (2015) Neuronal development in Caenorhabditis elegans is regulated by inhibition of an MLK MAP kinase pathway. Genetics 199:151-156.
Sharma J, Baker S, Turgeon S, Gurney A, Opperman K, and Grill B. (2014) Identification of a peptide inhibitor of the RPM-1/FSN-1 ubiquitin ligase complex. Journal of Biological Chemistry 289: 34654-34666.
Tulgren E, Turgeon S, Opperman K, and Grill B. (2014) The Nesprin family member ANC-1 regulates synapse formation and axon termination by functioning in a signaling pathway with RPM-1 and beta-Catenin. PLoS Genetics e1004481. doi: 10.1371/journal.pgen.1004481.
Baker ST, Opperman KJ, Tulgren ED, Turgeon SM, Bienvenut W, Grill B (2014). RPM-1 uses both ubiquitin ligase and phosphatase-based mechanisms to regulate DLK-1 during neuronal development. PLoS Genetics e1004297. doi:10.1371/journal.pgen.1004297.
Opperman KJ, and Grill B (2014). RPM-1 is localized to distinct subcellular compartments and regulates axon length in GABAergic motor neurons. Neural Development doi: 10.1186/1749-8104-9-10.
Awards, Recognition, Appointments, and Honors1998 Dean’s Silver Medal in Science (awarded for academic achievement), University of Alberta 1998 Post graduate scholarship National Science and Engineering Research Council (NSERC) 2000 Post graduate scholarship Canadian Institutes of Health Research (CIHR)
2004 Post-doctoral Fellowship Canadian Institutes of Health Research (CIHR)