Engineering the Corticospinal Tract as a High-Throughput Model to Study Spinal Cord Injury
Lawrence Recht, M.D., Stanford University
Professor of Neurology, Stanford University School of Medicine
James Weimann, Ph.D., Stanford University
Senior Research Scientist, Department of Neurology

One of the most important causes of morbidity after spinal cord injury (SCI) results from interruption of the corticospinal tract’s axonal projections. Furthermore, despite intensive study involving a number of strategies, it has been very difficult to reestablish these connections; therefore, complete recovery, even in animals, remains very infrequent.

The corticospinal pathway is precisely laid down during development, a process characterized by accurate axon guidance and plasticity that results from the interplay of a finite number of morphogens and guidance molecules. If one wants to manipulate this system so as to study the impact of a candidate molecule on spinal tract repair, the favored method is to develop transgenic mouse lines. The limiting factor in such an approach is the time required to develop each mouse line, creating a huge obstacle to rapid study of the multiple candidates that currently are postulated to play a role in this process.

We propose an alternative strategy using a stem cell based system in which ES cells that have been engineered in vitro to conditionally express desired genes can be preconditioned to differentiate into corticospinal motoneurons after transplantation into the neonate. Since these cells and their projections persist at least until early adulthood, it offers an opportunity to assess the synchronous impact of multiple genes on spinal cord repair in the adult. A proof of principle experiment is proposed in which a combination of genes potentially involved in either rejuvenating intrinsic growth state or clearing

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