Significant gaps exist in our understanding of the molecular and cellular controls that regulate neuronal positioning and the subsequent neurite elaborations that establish neural circuits. The Reelin-Dab1 pathway is required for neuronal lamination and dendritogenesis. New insights into the neuronal response to Reelin will expand our understanding of the cellular control of brain lamination and dendrite expansion. Our preliminary findings show that Stk25 is a modifier of this pathway that localizes to the Golgi, interacts with the LKB1- STRAD cell polarity pathway, and regulates neuronal polarization. Stk25 overexpression causes multiple axon formation, which is suppressed by Reelin signaling, and also suppresses a newly identified response to Reelin: the deployment of the Golgi into dendrites. These new findings suggest competitive roles for Reelin-Dab1 signaling and Stk25 in the regulation of neuronal polarization and Golgi deployment. Based on this, we hypothesize that competition among Reelin-Dab1, Stk25 and LKB1-STRAD signaling instructs neuronal lamination and dendritogenesis, in part by regulating Golgi deployment. This hypothesis will be addressed by pursuing the following specific aims: 1. Determine if LKB1-STRAD-STK25 signaling antagonizes Reelin-Dab1 signaling to instruct brain lamination, dendritogenesis, and Golgi deployment during development. 2. Determine if effectors of brain lamination and neuronal polarization regulate Golgi deployment. By manipulating Stk25 and LKB1-STRAD expression in wild-type and dab1-deficient brains, it will be determined how these genes instruct neuronal lamination and/or dendritogenesis. Known effectors of Reelin-Dab1 and Stk25 signaling will be investigated for roles in Golgi deployment to uncover the molecular control of this activity, which will provide essential information towards resolving its role in neuronal development. The proposed research will offer insight into how two competing pathways regulated by extracellular signals instruct brain lamination and dendritogenesis in vivo. In addition, it will provide novel clues about the molecular control of dendritic Golgi deployment.
Deficiencies in REELIN and STRAD (LYK5) cause mental retardation and epilepsy. These genes encode proteins that regulate distinct pathways important for neuronal lamination and polarization, processes critical for brain development. Here we will provide new insights into the regulation of brain organization by investigating antagonistic influences of these pathways on neuronal development based on evidence that Stk25 is a modifier of Reelin signaling that interacts with STRAD.
