The reeler mouse (a mouse whose reeler gene is defective) is characterized by motor coordination defects and tremors that result from errors in cell migration during development of the cerebral cortex and cerebellar cortex, both in the brain. Reelin, the protein missing in reeler mice, binds to lipoprotein receptors (VLDL/ApoE2), leading to phosphorylation of the intracellular protein Disabled-1 (Dab1). Mice missing either Dab1 or VLDL/ApoE2 receptors have anatomical and behavioral defects virtually identical to those of reeler mice, as these three molecules function in a common signaling pathway.
Dr. Phelps's lab has provided the first evidence that reeler mutants also have profound sensory defects, including mechanical insensitivity and increased thermal sensitivity. The first aim of this proposal is to determine if mice lacking Dab1 or VLDL/ApoE2 receptor also have defects in pain sensation. The second aim is to study the migratory errors that cause the abnormal sensory processing. Preliminary results suggest that part of the spinal cord (the superficial dorsal horn) in reeler mice contains mispositioned neurons. To prove that these migratory errors are caused by Reelin deficiency, the Reelin signaling pathway will be blocked with the goal of recapitulating the migratory errors in a culture dish. To further link the defects in pain processing with anatomical rearrangements, experiments will be conducted to determine which neurons along the pain processing pathway are responsible for the sensory defects. These studies will focus on the primary sensory neurons that detect pain and their targets in the dorsal horn of the spinal cord. Finally, the basic migratory patterns that establish dorsal horn lamination will be examined.
This proposal continues activities initially funded by an NSF Early Career Award. Integration of research and teaching activities includes teaching an undergraduate class on the principles of nervous system development and disseminating multimedia material developed for this class in the California Digital Library. Additionally, minority students have and will continue to conduct research in the Phelps' laboratory.
