Altered Nociception and Neuronal Migration in the Dorsal Horn of Reeler Mice

主要研究者：Dr. Patricia E. PhelpsTitle: reeler小鼠背角痛觉和神经元迁移的改变Grant Number: iob -0518714 reeler小鼠（一种reeler基因有缺陷的小鼠）的特征是运动协调缺陷和震颤，这是由于大脑皮层和小脑皮层发育过程中细胞迁移错误造成的。Reelin，在reeler小鼠中缺失的蛋白质，与脂蛋白受体（VLDL/ApoE2）结合，导致细胞内蛋白Disabled-1 （Dab1）磷酸化。缺少Dab1或VLDL/ApoE2受体的小鼠在解剖学和行为学上的缺陷与reeler小鼠几乎相同，因为这三种分子在共同的信号通路中起作用。菲尔普斯的实验室提供了第一个证据，证明卷轴突变体也有严重的感官缺陷，包括机械不敏感和热敏感性增加。这项提议的第一个目的是确定缺乏Dab1或VLDL/ApoE2受体的小鼠是否也有痛觉缺陷。第二个目的是研究导致感觉加工异常的迁移误差。初步结果表明，reeler小鼠的部分脊髓（浅背角）含有错误定位的神经元。为了证明这些迁移误差是由Reelin缺乏引起的，我们将阻断Reelin信号通路，目的是在培养皿中重现迁移误差。为了进一步将疼痛处理缺陷与解剖重排联系起来，将进行实验以确定疼痛处理通路上的哪些神经元负责感觉缺陷。这些研究将集中于检测疼痛的初级感觉神经元及其在脊髓背角的目标。最后，建立背角层压的基本迁移模式将被检查。该提案继续了最初由美国国家科学基金会早期职业奖资助的活动。研究与教学活动的整合包括教授一门本科生神经系统发育原理的课程，并在加州数字图书馆传播为这门课程开发的多媒体材料。此外，少数族裔学生已经并将继续在菲尔普斯的实验室进行研究。

Principal Investigator: Dr. Patricia E. PhelpsTitle: Altered nociception and neuronal migration in the dorsal horn of reeler mice Grant Number: IOB-0518714The 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.