L1 is an axonal cell adhesion molecule (CAM) that is highly expressed on growing axons during development but decreases to low levels by adulthood. Ll CAM is highly conserved in mammals, and related molecules are found in diverse species, suggesting a conservation of its function in axonal pathfinding and fasciculation. L1 is expressed by olfactory ensheathing glia (OEG) and Schwann cells, both of which facilitate axon regeneration. In addition, Ll is re-expressed on regenerating axons in the hippocampal formation. Thus, Ll is an excellent candidate for an adhesion type molecule of critical importance to regenerating spinal cord axons.
Specific Aim 1 is to determine the supraspinal target of a population of GABAergic commissural neurons that express Ll on the surface of their axons. Subsequent experiments will examine the axonal pathfinding of these commissural neurons in Ll knockout mice.
Specific Aim 2 seeks to determine if Ll is re-expressed on adult axons as they regenerate new processes after spinal cord injury (SCI). Following a complete midthoracic spinal cord transection at postnatal day 5, we have preliminary data suggesting that Ll is re-expressed in axons both rostral and caudal to the lesion three months post injury. We will characterize the temporal expression of Ll on axons relative to the time post injury to provide information regarding potential axon sprouting after SCI. Furthermore, we will test if training spinal transected animals in spinal stepping patterns will change the level of Ll expression on lesioned axons.
In Specific Aim 3, an OEG transplantation model will be used to determine if ascending sensory axons are able to project to their targets and if ascending and descending regenerating axons will re-express Ll CAM as they cross the transection site. Spinal transected animals will be transplanted with Ll-expressing OEG cells, whereas the controls will be injected with media. This OEG transplantation model has been shown by others to dramatically improve voluntary motor function in adult animals with SCI. Our long term goal is to develop a regeneration model for SCI that restores the ascending projections from commissural neurons.
