The goal of this research proposal is to examine how the interactions of the various neurotrophin receptors influence retrograde signaling once the receptors are activated. Investigation into the molecular mechanisms of these protein-protein interactions will enhance our understanding of the manner in which these molecules serve to participate in a wide range of nervous system phenomena; including developmentally regulated programmed cell death, synaptic contact and remodeling, and retrograde signaling. The purpose of this grant is fourfold. Using a Campenot chamber which will mimic the in vivo situation in a culture system, we will analyze whether p75 enhances retrograde axonal signaling more substantially than signaling thru the cell body. Trk autophosphorylation and MAP kinase activation as well as the interactions of p75/MAP kinase and trk/MAP kinase will be assessed. Next, we will map the MAP kinase binding domains on p75 and the trk receptors to determine if which mutations prevent p75 enhancement of p75/MAP kinase or trk/MAP kinase interactions. Finally, we intend to assess the retrograde transport of these receptor/MAP kinase complexes to the neuron cell body following receptor activation at the nerve terminal. These investigations will further decipher the complex interactions and mechanisms of the retrograde signaling process.
