Center for Molecular Neurobiology

Anthony Young, PhD, Director

The mission of the Center for Molecular Neurobiology is to reach the highest echelons of scholarship by performing quality basic research and providing superior training in developmental, cellular and molecular neuroscience. Research strengths include the use of three molecular genetic model systems (mice, zebra fish and Drosophila) as well as research directly applicable to humans. This is an intercollegiate program whose faculty have joint appointments in the Center as well as in departmental tenure-initiating units. They can thus contribute to the missions of their departmental units and form bridges between the Center and departments within separate colleges.

Ongoing Research Programs

Christine Beattie, PhD, studies molecular mechanisms controlling vertebrate axon guidance during development and motor neuron degeneration in spinal muscular atrophy and amyotrophic lateral sclerosis using zebra fish as a model system.
Anthony Brown, PhD, uses molecular, biochemical and imaging approaches to study the assembly and axonal transport of neurofilaments.
Tsonwin Hai, PhD, studies the role of the stressinducible transcription factor ATF3 in diabetes and cancer.
Paul Henion, PhD, studies molecular regulation of embryonic cell diversification and cell fate specification, proliferation, survival and differentiation in the nervous system.
Jeff Kuret, PhD, employs molecular, cellular and pharmacological methods to investigate Alzheimer disease pathogenesis. His work focuses on biochemical mechanisms in the formation of lesions that are the hallmarks of the disease, and on development of inhibitors of lesion formation as potential therapeutics.
Sung Ok Yoon, PhD, studies molecular mechanisms of growth factor-mediated action in the nervous system, with a focus on regulation of cell survival and apoptosis under pathological conditions.

Research Accomplishments of 2006

During cancer development, stress signals designed to eliminate tumorigenic cells are encountered. Cancer cells that survive this process have managed to foil the hardwired stress response. Studies by Tsonwin Hai, PhD, and associates have shed light on this process by showing that ATF3, a gene that normally eliminates cells as part of the stress response, is co-opted to become an oncogene, and that this phenomenon may play an important role in breast cancer progression. In addition, they have found that ATF3 acts as a mediator for cancer cells to respond to stromal signals. Thus, ATF3 transmits the signals to the transcriptional networks and elicits dichotomous responses.
James Jontes, PhD, has developed a novel cell model to explain how connections among the trillions of synapses in the central nervous system are formed. The model involves formation of nonspecific prosynaptic interactions followed by specific synapses through recruitment of bona fide specific adhesion molecules via changes in intracellular trafficking to generate reproducible patterns of synaptic connectivity. His laboratory is testing this hypothesis and the role of the cadherin family of adhesion molecules through analysis of the developing zebra fish nervous system.
Through behavioral studies using “knock-out” mice, John Oberdick, PhD, has found that L7/PcP2, a protein expressed in cerebellar Purkinje cells, plays an essential role in sensorimotor function. At the biochemical and physiological levels, Oberdick and Michael Zhu, PhD, have found that L7/PcP2 functions as a modulator of G protein signaling, and that L7 fine-tunes the activity of voltage-gated calcium channels (Cav 2.1) through G proteins. Oberdick and Zhu postulate that disruption of L7 function may play a role in certain behavioral disorders in humans.

Research Accomplishments of 2005

Spinal muscular atrophy (SMA) is a motoneuron degenerative disease caused by mutations that alter expression and/or function of the survival motoneuron gene (smn). Christine Beattie, PhD, and colleagues are using zebrafish as a vertebrate model to deduce mechanism(s) by which a defective smn gene produces neuronal degeneration. Because the zebrafish embryo is transparent and amenable to molecular manipulations, it is suited for the study of developmental disorders. The smn protein is ubiquitously expressed and has been implicated in RNA complex formation (snRNP) in all cells. Hence, it is paradoxical that low smn protein levels compromise motoneurons. Using protein knockdown technology, researchers decreased the amount of smn present during zebrafish development and found dramatic defects in motor axon outgrowth and guidance. In particular, motor axons were truncated and excessively branched. This is the first time smn has been shown to function in motor axon outgrowth in vivo and suggests that motoneuron cell death in SMA may be caused by motor axon defects during early development. By adding back human mRNA encoding either wild-type or mutant smn protein, the Beattie lab has dissociated the general snRNP functions of smn from its effect on motor axons. Thus, disruption of an activity of the smn protein unique to motor axons may produce SMA.
ATF3 is a stress-inducible gene that encodes a member of the ATF/CREB family of transcription factors. Tsonwin Hai, PhD, and colleagues studied the roles of ATF3 in cell death and cell cycle regulation. Mouse fibroblasts deficient in ATF3 (ATF3-/-) were partially protected from ultraviolet-induced apoptosis, and fibroblasts ectopically expressing ATF3 under an inducible system exhibited features characteristic of apoptosis upon ATF3 induction. Furthermore, ATF3-/- fibroblasts transitioned from the G1 to the S phase of the cell cycle more efficiently than the ATF3+/+ (wild type) fibroblasts, suggesting a growth arrest role of ATF3. Consistent with the growth arrest and pro-apoptotic roles of ATF3, ATF3-/- fibroblasts transformed with the Ras proto-oncogene exhibited higher growth rate, produced more colonies in soft agar and formed larger tumors upon xenograft injection than the ATF3+/+ counterparts. ATF3-/- cells, either with or without Ras transformation, had increased Rb phosphorylation and higher levels of various cyclins. Significantly, ATF3 bound to the cyclin D1 promoter as shown by chromatin immunoprecipitation (ChIP) assay and repressed its transcription by a transcription assay. This indicates that ATF3 promotes cell death and arrest, and suppresses Ras-mediated tumorigenesis.
Cytoskeletal and cytosolic proteins move along axons as slow components of axonal transport, but the mechanism is not well understood. Studies by Anthony Brown, PhD, and colleagues on the movement of green fluorescent protein (GFP)-tagged neurofilament proteins in cultured neurons have shown that the slow rate of neurofilament transport is an average of rapid bidirectional movements interrupted by prolonged pauses. In prior studies on cultured rat sympathetic neurons, the Brown lab found that green fluorescent protein-tagged neurofilament proteins move predominantly in filamentous structures; re-searchers proposed that these structures are single-neurofilament polymers. Brown tested this by using a rapid perfusion technique to capture these structures as they move through natural gaps in axonal neurofilament. Because the gaps lack neurofilaments, they permit unambiguous identification of the captured structure. Using quantitative immunofluorescence microscopy and correlative light and electron microscopy, researchers showed that the captured structures are single continuous neurofilament polymers. Thus, neurofilament polymers are one of the cargo structures of slow axonal transport.

OSU Center for Molecular Neurobiology
206 Rightmire Hall
1060 Carmack Road
Columbus, OH 43210