James B. Rand, Ph.D.
Member and Program Chair
Genetic Models of Disease Research Program
H.A. and Mary K. Chapman Chair in Medical Research
Adjunct Professor, Department of Cell Biology, University of Oklahoma Health Sciences Center
Adjunct Professor, Oklahoma Center for Neuroscience
To understand the whole, you need to understand the pieces. You wouldn’t put a bike together without knowing what the wheels and the chain and handlebar do, so we can’t truly understand how the human body works until we understand how the nerves function.
In my lab, we study how nerves send and receive signals and what problems can keep those signals from getting through or end up going to the wrong place. One tool we use is a microscopic worm, called a C. elegans. The reason we use them is that, unlike larger animals, we know everything about these little worms because they’re so simple. We even know exactly how many cells are in their nervous systems – 302.
By studying genetic abnormalities in C. elegans, we can make some observations about how genetics play a role in human nervous systems. Some genes keep the worms from functioning normally, which can tell us a lot about how problems with nerve communication in human brains are caused and, hopefully, how we can treat them.
B.A., Hofstra University, Hempstead, NY (cum laude), 1969
Ph.D., The Rockefeller University, New York, 1975
Honors and Awards
1964-1969 National Merit Scholar
1969-1971 NSF Graduate Fellowship
1975 Gosney Foundation Postdoctoral Fellowship
1976-1977 American Cancer Society Postdoctoral Fellowship
1978 Muscular Dystrophy Association Postdoctoral Fellowship
1995 Edward L. and Thelma Gaylord Prize for Scientific Achievement
1996-2001 Merrick Distinguished Research Scientist
2001-present H.A. and Mary K. Chapman Chair in Medical Research
Serves on NIH Reviewers Reserve; reviews manuscripts for Genetics; reviews grants for National Science Foundation.
Society for Neuroscience
Genetics Society of America
International Society for Autism Research
Joined OMRF Scientific Staff in 1989.
For more than 20 years, we have been using the soil nematode Caenorhabditis elegans to identify and characterize synaptic proteins, and to determine how mutational loss of these proteins leads to altered behaviors. The simple, 302-cell nervous system of C. elegans is well suited for such studies because we can apply powerful tools of genetics, cell biology, and molecular biology to analyze the structure and function of the nervous system. In fact, numerous studies (including many from our laboratory) have shown that C. elegans neuronal proteins are structural and functional homologs of the corresponding mammalian proteins, and it is now well established that C. elegans provides a powerful model for analyzing synapse structure, function, and development.
In the past, we have studied genes and proteins involved in the transport of specific neurotransmitters or groups of neurotransmitters, as well as genes and proteins involved in the general release mechanism of all neurotransmitters. Recently, we have begun to study molecules involved in synapse formation, using C. elegans mutants with aberrant synapse structural components as a model for the study of autism and autism spectrum disorders (ASDs). These are developmental disorders associated with atypical socialization, communication, and behavior, and are often accompanied by sensory deficits and abnormalities in sensory processing, cognitive function, and learning. A recent study released by the Centers for Disease Control and Prevention (CDC) reported that the prevalence of ASDs is increasing, and they now affect approximately one in every 110 children.
Although environmental factors clearly play a role in the etiology and severity of ASDs, family studies have shown that ASDs also have a strong hereditary (i.e., genetic) basis, apparently involving a large number of genes. One of the most striking results emerging from the intensive international effort to identify such “autism-related” genes has been the demonstration of an association with autism (in some families) of mutations in genes encoding synaptic proteins. Thus far, the best-studied of these autism-associated genes and proteins are the genes encoding neuroligins. Neuroligins are adhesion/signaling proteins present on post-synaptic cell membranes, and they bind specifically to a set of presynaptic membrane proteins called neurexins. There are 4 neuroligin-encoding genes in humans, and mutations disrupting NLGN3 and NLGN4 are associated with ASDs.
Taking advantage of our experience studying synapse development and function, we have begun to investigate the properties of neuroligin in C. elegans and the cellular and behavioral consequences of neuroligin-deficient mutations.C. elegans has a single neuroligin-encoding gene (nlg-1), and we have shown that the protein it encodes is quite similar to mammalian neuroligins. Null nlg-1 mutants (lacking all protein function) are viable and superficially wild-type in their appearance, development and behavior. In addition, the nervous system of nlg-1 mutants is grossly normal. Upon closer inspection, however, nlg-1 mutants display subtle sensory deficits, including a lack of sensitivity to some chemicals, insensitivity to changes in temperature, and altered processing of simultaneous sensory inputs. Such sensory abnormalities mirror many anecdotal reports from families as well as some research on children and adolescents with ASDs.
During the course of our studies on neuroligin mutants in C. elegans, we discovered that, in addition to sensory deficits, these mutants have increased levels of oxidative stress. This was unexpected, because mutations in synaptic proteins had not previously been associated with oxidative stress. It was also noteworthy because of studies documenting increased oxidative stress in individuals with autism. Although we do not yet understand the exact mechanism by which the loss of neuroligin leads to oxidative stress, it is striking that a mutation which, in humans, is associated with autism should produce a similar oxidative stress phenotype in C. elegans. What is still needed, however, is a detailed understanding of the mechanisms by which perturbations of synaptic proteins lead to specific metabolic deficits as well as to alterations of cells and circuits within a functioning nervous system.
Autism and Oxidative Stress: Correlations, Models, and Causality. Although a number of studies have been published demonstrating elevated markers of oxidative stress in individuals with ASDs, the nature of the possible relationship between autism and oxidative stress has never been clear. At best, such studies provide no more than a correlation between oxidative stress and ASDs, yet a model often proposed is that oxidative stress (perhaps resulting from environmental toxins) somehow causes or contributes to the etiology of ASDs. Our studies in C. elegans demonstrate that loss of the synaptic protein neuroligin is not merely correlated with oxidative stress, but it actually causes the oxidative stress. Therefore, if oxidative stress is a consequence of aberrant synaptic proteins in nematode neurons, then it seems plausible to expect that aberrations of synaptic proteins in human neurons might have similar consequences. This raises the intriguing possibility that in humans, specific types of neuronal disruption (such as mutations affecting synaptic adhesion proteins) might be the cause, rather than the result, of oxidative stress.
Mathews EA, Mullen GP, Hodgkin J, Duerr JS, Rand JB. Genetic Interactions between UNC-17/VAChT and a Novel Transmembrane Protein in Caenorhabditis elegans. Genetics 192:1315-1325, 2012. [Abstract]
Mullen GP, Grundahl KM, Gu M, Watanabe S, Hobson RJ, Crowell JA, McManus JR, Mathews EA, Jorgensen EM, Rand JB. UNC-41/Stonin functions with AP2 to recycle synaptic vesicles in Caenorhabditis elegans. PLoS One 7:e40095, 2012. [Abstract]
Hunter JW, Mullen GP, McManus JR, Heatherly JM, Duke A, Rand JB. Neuroligin-deficient mutants of C. eleganshave sensory processing deficits and are hypersensitive to oxidative stress and mercury toxicity. Dis Model Mech 3:366-376, 2010. [Abstract]
Mullen GP, Mathews EA, Vu MH, Hunter JW, Frisby DL, Duke A, Grundahl K, Osborne JD, Crowell JA, Rand JB. Choline transport and de novo choline synthesis support acetylcholine biosynthesis in C. elegans cholinergic neurons. Genetics 177:195-204, 2007. [Abstract]
Mathews EA, Mullen GP, Crowell JA, Duerr JS, McManus JR, Duke A, Gaskin J, Rand JB. Differential expression and function of Synaptotagmin 1 isoforms in Caenorhabditis elegans. Mol Cell Neurosci 34:642-652, 2007. [Abstract]
Rand JB. Acetylcholine. In WormBook 1-21, 2007. [Abstract]
Sandoval GM, Duerr JS, Hodgkin J, Rand JB, Ruvkun G. A genetic interaction between the vesicular acetylcholine transporter VAChT/UNC-17 and synaptobrevin/SNB-1 in C. elegans. Nat Neurosci 9:599-601, 2006. [Abstract]
Mullen GP, Mathews EA, Saxena P, Fields SD, McManus JR, Moulder G, Barstead RJ, Quick MW, Rand JB. TheCaenorhabditis elegans snf-11 gene encodes a sodium-dependent GABA transporter required for clearance of synaptic GABA. Mol Biol Cell 17:3021-30, 2006. [Abstract]
Zhu H, Duerr JS, Varoqui H, McManus JR, Rand JB, Erickson JD. Analysis of point mutants in the Caenorhabditis elegans vesicular acetylcholine transporter reveals domains involved in substrate translocation. J Biol Chem 276:41580-41587, 2001. [Abstract]
Genetic Models of Disease Research Program, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104
Phone: (405) 271-7681
Fax: (405) 271-7312