Altered nociception and neuronal migration

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

"This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)." Reelin, the protein missing in reeler mice, binds to lipoprotein receptors (VLDL/ApoE2) and causes phosphorylation of the intracellular protein Disabled-1 (Dab1). Mice with mutations in Reelin, VLDLR and ApoER2, or Dab1 have similar migratory errors in the superficial dorsal horn of the spinal cord, the termination site for primary sensory neurons that convey pain information into the central nervous system. Previous studies by the principal investigator's laboratory found a functional correlate of these developmental defects: an increased sensitivity to heat and a decreased sensitivity to mechanical pain. The differential effects observed on these pain modalities suggested that Reelin-signaling pathway mutants naturally segregate the biological basis of thermal and mechanical pain transmission. The first aim of this project is to identify the mis-positioned neurons in the dorsal horn of Reelin-signaling pathway mutants using a "knock-in" mouse line with a blue reporter gene (beta-galactosidase) inserted in the Dab1 locus. Once the positioning errors in reeler and dab1 mutant dorsal horns are identified, they will use embryonic slice cultures to study the migratory defects in the mutant dorsal horn. The second aim will link the migratory errors to thermal nociceptive processing. Anatomical, behavioral, and perturbation experiments will determine if the heat hypersensitivity found in mutants is caused by mis-positioned neurons in the superficial dorsal horn that bear Neurokinin1 (NK1) receptors. Because the NK1 receptor is the target of the substance P-releasing nociceptors, it is expected that the ectopic NK1-expressing cells within the superficial dorsal horn are likely responsible for the heat hypersensitivity in Reelin-signaling pathway mutants. Two undergraduate student researchers and a post-doctoral fellow will receive mentoring and research training as they conduct experiments related to this project. The broader impact will be to facilitate integration of research and teaching activities in developmental neurobiology and to support undergraduate and minority education and training in research careers.