INDIVIDUAL RESEARCHERKenneth R. Norman , Ph.D.
Education2000 - Ph.D. from University of British Columbia
The versatile signaling molecule calcium (Ca2+) is required for many cellular functions required for life including fertilization, cell proliferation, secretion, transcription, metabolism and muscle contraction. Paradoxically, Ca2+ is also involved in cell death, and excitotoxicity in the nervous system. Therefore, the regulation of intracellular Ca2+ levels is critical for cellular function and survival. Unlike other signaling molecules, Ca2+ cannot be degraded, synthesized or modified, and yet calcium levels are dynamically modulated. Thus, many proteins are required for the proper regulation of intracellular Ca levels. Our research has focused on the interesting biological question of how Ca2+ is regulated at the cellular level, and how Ca2+ dysregulation affects animal behavior and development. Thus far, we have focused on several gene products and their regulation of Ca2+ oscillations in the soil nematode, Caenorhabditis elegans. C. elegans has a number of features that make it an outstanding model system for elucidating cell signaling mechanisms. First, C. elegans is readily grown in the laboratory on a diet of Escherichia coli. Second, it proliferates rapidly, within three days C. elegans develops from a fertilized egg to an adult. Furthermore, an individual adult can produce 300 progeny, which enables large-scale production of several million worms per day. Third, C. elegans is transparent so development of muscle, intestine and the nervous system can be easily observed. Moreover, with the use of fluorescent markers, changes in Ca2+ dynamics as well as protein localization at the subcellular level can be readily determined in living animals. Lastly, C. elegans homologues have been identified for 60-80% of human genes. Thus far, we have found that VAV-1, a homolog of the proto-oncogene Vav, acts to regulate intracellular Ca2+ oscillations via the Rho GTPases and IP3 signaling. In VAV-1 mutants, as well as these downstream effectors, several rhythmic behaviors are disrupted. These include pharyngeal muscle pumping, which is required for feeding, gonadal sheath cell contractions and spermatheca dilation, which are required for fertilization, and the defecation motor program, which consists of three motor steps that occur every 45 seconds. These data suggest that VAV-1 acts as a master regulator of biological rhythms. Using these simple rhythmic behaviors as a model system, our long-term research goal is to identify the mechanisms that regulate intracellular Ca2+ signaling and determine the cell signaling pathways that regulate rhythmic behaviors. Specifically, our research will focus on addressing the following questions: 1) What are the molecular events required to stimulate VAV-1 signaling and rhythmic behavior? 2) What are the other gene products involved in VAV-1 and Ca2+ signaling?
- Norman KR, Maricq AV. Innexin function: minding the gap junction. Curr Biol. 2007 Sep 18;17(18):R812-4.
- Norman KR, Cordes S, Qadota H, Rahmani P, Moerman DG. UNC-97/PINCH is involved in the assembly of integrin cell adhesion complexes in Caenorhabditis elegans body wall muscle. Dev Biol. 2007 Sep 1;309(1):45-55.
- Norman KR, Fazzio RT, Mellem JE, Espelt MV, Strange K, Beckerle MC, Maricq AV. The Rho/Rac-family guanine nucleotide exchange factor VAV-1 regulates rhythmic behaviors in C. elegans. Cell. 2005 Oct 7;123(1):119-32.
- Mackinnon AC, Qadota H, Norman KR, Moerman DG, Williams BD. C. elegans PAT-4/ILK functions as an adaptor protein within integrin adhesion complexes. Curr Biol. 2002 May 14;12(10):787-97.
- Norman KR, Moerman DG. Alpha spectrin is essential for morphogenesis and body wall muscle formation in Caenorhabditis elegans. J Cell Biol. 2002 May 13;157(4):665-77.