The overall aim of this proposal is to dissect the physiological relevance of the different pathways activated by p75ntr and to elucidate novel functions using a genetic approach combining in vitro and in vivo studies. We hypothesize that p75ntr has the ability to generate diverse, and sometimes contradicting, signals depending on the cell context and the nature of the activating ligand. In order to tackle the complexity of p75ntr function, we propose a structure-function approach to dissect those different signals, and a genetic approach to investigate their biological importance in relevant cell types, both in vitro and in vivo. In order to reveal novel p75ntr functions, we will generate gain-of-function alleles of this receptor and characterize their function in cell lines and primary cultures, and in vivo by knock-in expression in transgenic mice. Currently, only loss-of-function models for investigating in vivo roles of p75ntr are available, the analysis of which may be complicated by redundant and compensatory pathways. A gain-of-function approach may help to reveal novel in vivo functions of this receptor. In order to dissect the physiological relevance of the different pathways activated by p75ntr, we will generate loss-of-function alleles of this receptor capable of activating some pathways but not others, and characterize their function in vitro and in vivo by knock-in expression in transgenic mice. Further mechanistic and functional insights may be obtained by combining distinct sets of gain- and loss-of-function mutations in individual p75ntr molecules. We suggest that these types of studies will help to link distinct signaling pathways and downstream effectors to specific biological activities and phenotypes. Given the overall medical importance of the ligands, signaling pathways and biological activities of p75ntr, a better understanding of the mechanisms and in vivo functions elicited by this receptor is essential, particularly as agonists and antagonists are being considered for therapeutic purposes in nerve damage, stroke and neurodegenerative diseases.