Most axons in the adult mammalian central nervous system (CMS) are unable to regenerate after injury, potentially leading to devastating and permanent functional deficits. It has been proposed that the failure in axon regeneration could be due to both a reduced intrinsic regenerative capacity of mature neurons, and to a hostile environment of the adult CMS, including both the presence of inhibitory factors from both the glial scar and CMS myelin and a lack of neurotrophic support. Despite recent progress in identifying some molecular players in each of these processes, how these extrinsic and intrinsic factors determine the regenerative decision of lesioned axons in vivo remains largely unknown. In addition, it remains to be determined whether all CMS axons differ in their requirements for successful axon regeneration. Recent studies from our laboratory as well as others have demonstrated that three proteins, Nogo, myelin associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp), collectively account for the majority of the inhibitory activity associated with CMS myelin. Interestingly, all three proteins exert their inhibitory actions through a common receptor complex consisting of the ligand-binding Nogo receptor (NgR) and two signal-transducers p75 and a newly identified component Lingo-1. These observations offer a unique possibility for designing reagents to block the inhibitory influences of CNS myelin by blocking this common signaling pathway. Thus, we have generated transgenic mice that stably express this dominant-negative NgR in the nervous system and demonstrated that the neuronal responses to myelin inhibitors are blocked in the neurons from these transgenic lines. These animal models will be used in this study to define the role of myelin inhibitors and other intrinsic and extrinsic factors in limiting the regeneration of different axonal tracts in vivo