Kenneth R. Norman
University of British Columbia
Research in the Norman Lab focuses on the genetic pathways and molecular mechanism that regulate animal behavior. Our studies utilize the free-living nematode Caenorhabditis elegans, a model system that provides exceptional experimental advantages for describing fundamental biological processes. These advantages include genetic tractability, small nervous system with mapped neuronal connectivity, transparent (individual cells can be visualized in vivo), stereotyped behaviors, and efficient methods for studying large numbers of animals. Our research employs in vivo calcium signaling in concert with genetic, optogenetic, molecular and cell biological techniques to explore organismal behavior. Listed below are the current specific areas of research in the lab:
1. The role of VAV-1 in calcium regulation.
Rhythmic activities are ubiquitous biological phenomena and can be observed in cells, tissues, and the behavior of most organisms. Biological rhythms regulate many diverse processes, such as heartbeat, breathing, locomotion, and gut peristalsis. The molecular machinery underlying the generation and regulation of rhythms less than a day in duration—known as ultradian rhythms—are not well understood. We have found that the C. elegans Rho GTPase family guanine nucleotide exchange factor, VAV-1, has a crucial role in several rhythmic behaviors. The VAV-1 signaling pathway controls rhythmic behaviors by dynamically regulating intracellular calcium oscillations. Our ongoing studies are focused on identifying other gene products that contribute to the VAV-1 signaling pathway, in the regulation of and generation of calcium oscillations.
2. The role of VAV-1 in the regulation of locomotory behavior and behavioral quiescence.
In addition to having a role in calcium oscillations, we have found that VAV-1 acts in a neural circuit to negatively regulate the rate of motor activity during awake and sleep-like states. Specifically, VAV-1 acts in a single neuron, called ALA, to 1) regulate motor circuit activity in adult animals and 2) mediate behavior quiescence during lethargus (a sleep-like state) and 3) EGF induced quiescence. Moreover, our studies indicate that VAV-1 activity in ALA repress the activity of postsynaptic command interneurons, which regulate locomotion by processing and transmitting signals from sensory neurons to motor neurons. Thus, we have identified a novel neural network that is involved in negatively regulating motor activity during awake and sleep-like states in C. elegans. Furthermore, we have implicated VAV-1 as a downstream effector of EGF signaling in the nervous system. Our on going studies are investigating the molecular mechanisms VAV-1 has in the ALA neuron to repress command interneuron activity.
3. Regulation of epithelial calcium oscillations.
Calcium is a versatile signaling molecule that is required for many cellular functions, e.g. fertilization, cell proliferation, transcription, metabolism and muscle contraction. Paradoxically, calcium is also involved in cell death and excitotoxicity in the nervous system. Thus, the regulation of intracellular calcium levels is critical for cellular function and survival. In our lab, we are investigating the signaling pathways that regulate a simple rhythmic behavior in C. elegans that is synchronized by oscillatory intracellular calcium levels. Presently, we are investigating a class of potassium channels, Kv7, and their role in mediating calcium oscillations. We have found that phospholipase C beta and calcium/calmodulin-dependent kinase II have a role in regulating Kv7 channel activity in the regulation of calcium oscillation in the intestinal epithelial cells of C. elegans.
4. The role of presenilin in calcium regulation and mitochondria function.
Alzheimer’s disease is the most frequent form of dementia that is characterized by progressive memory loss and cognitive dysfunction. Mutations in presenilins are the most common cause of early onset familial Alzheimer’s disease. Although altered presenilin function has been known to have a role in Alzheimer’s disease for ~ 20 years, the functional consequences of mutations in presenilins are controversial and not understood. Due to the complexity in understanding presenilin function, we are using C. elegans, a simple model system, to uncover the in vivo biological role of presenilins. We have discovered that mutations in sel-12, which encodes the C. elegans presenilin homolog, have elevated calcium signaling and perturbed mitochondria function and organization. Thus, we hypothesize that SEL-12 regulates intracellular calcium levels and that the increase in intracellular calcium leads to the dysfunction of the mitochondria.We are using a multifaceted approach to test this hypothesis, which includes in vivo measurements of mitochondria morphological dynamics, analysis of mitochondrial function, genetic and molecular analyses, and pharmacological approaches to resolve the role presenilin has in the regulation of mitochondria function and calcium signaling in C. elegans.
- 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.