Christine E. Beattie, Ph.D.

Associate Professor
Department of Neuroscience and Center for Molecular Neurobiology

Degree: Case Western Reserve University
Postdoctoral Training: University of Oregon,
Dr. Judith Eisen

Phone: (614) 292-5113
Fax: (614) 292-7539
Email:beattie.24@osu.edu

Link to NLM PubMed publications list for Christine E. Beattie (last 10 years)

Research Area:

Genetic and molecular analysis of motor axon outgrowth during development and disease using zebrafish as a model system.

Current Research:

Our goal is to understand the genetic and molecular programs that enable motor axons to extend to the correct muscles during normal development and in motoneuron diseases. We use zebrafish as a vertebrate model organism due to its well characterized nervous system and its relatively simple neuromuscular organization. For example, during the first day of development only three primary motoneurons, CaP (caudal primary), MiP (middle primary) and RoP (rostral primary) motoneurons innervate the developing myotome. CaP extends a ventral axon, MiP a dorsal axon, and RoP innervates the region in-between. The process of axon outgrowth occurs due to the integration of signals from the environment received by the growth cone. Using forward genetics, we have identified two mutations that cause motor axons to stall and fail to extend into distal target regions.  Although these mutations have a similar phenotype, our analysis reveals that they are disrupting distinctly different aspects of motor axon guidance. One of these mutations, stumpy, causes all motor axon growth cones to stall at intermediate targets; regions along axon pathways where growth cones pause, branch, or turn suggesting that information is being imparted. Using genetic mosaics we show that Stumpy function is needed both in the neuron and in the environment. Our hypothesis is that Stumpy enables growth cones to proceed past intermediate targets, perhaps by a de-adhesive mechanism. To test this hypothesis, we are cloning stumpy to reveal its molecular identity. The other mutation, topped, has a very specific phenotype where the CaP motoneuron is severely delayed in growing into the ventral myotome. Genetic mosaic analysis revealed that Topped is functioning in the ventromedial fast muscle. These data suggest that topped is the ventral cue that enables motor axons to extend into the ventral myotome. This finding is significant in that it strongly supports the idea that growth cones recognize unique myotome regions based on the presence of particular molecules. In summary, by isolating specific mutations, we are genetically defining the steps that enable motor axons to reach their target muscles. Future studies will build on these genetic pathways by identifying interacting genes and cloning these genes will begin to reveal their biochemical mechanisms of action.

Our understanding of the genetics and development of motoneurons puts us in an excellent position to address the biological basis of motoneuron diseases. Currently, we are establishing zebrafish as a model system for studying Spinal Muscular Atrophy (SMA); a motoneuron degenerative disease caused by mutations in the survival motoneuron gene (smn). Although the ubiquitously expressed Smn protein has been implicated in RNA complex formation, it remains unclear why low Smn levels specifically compromises motoneurons. Using protein knockdown technology, we 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. By decreasing Smn in single motoneurons in living embryos, we found that Smn functions cell-autonomously with respect to motoneurons in this process. This is the first time that 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. Thus, our analysis has revealed a novel role for Smn. Future studies in the lab will focus on determining the mechanism of Smn function in motor axons. Furthermore, we plan to use this zebrafish model of SMA to screen for drugs to treat this devastating disease.

For more information, please visit Dr.Christine Beattie's personal webpage.