We have recently discovered a form of regenerative sprouting of cortico-spinal tract (CST) axons following spinal cord injury in mice. This regenerative sprouting, and perhaps other forms of axon regeneration, are enhanced in certain lines of mice in which genes encoding axon growth inhibitory molecules (Nogo) have been deleted. The local regenerative growth in normal mice and the enhanced growth in genetically modified mice is of the sort that could restore descending input to neuron pools mediating motor function near the site of injury. This form of growth could be especially important following lesions at the cervical level, where growth over a even single segment could restore function to motoneurons supplying critical muscle groups of the forelimb. These mice provide the opportunity to ask a key question that was previously impossible to address-whether limited CST regeneration is sufficient to restore voluntary (CST-mediated) motor function. In the present project, we will define the nature of the local axonal growth responses of CST axons that occur after spinal cord injury in normal mice, and test the hypothesis that this growth mediates recovery of function in segmental motor circuitry. We will quantify the time course and extent of regenerative CST sprouting following injuries at both the thoracic and cervical levels and in the same animals, assess whether recovery of hindlimb and forelimb motor function respectively occurs during the period of regenerative growth. These analyses will allow us to correlate the nature and extent of regenerative growth with functional outcome. To test the hypothesis that recovery is due to reinnervation, we will carry out parallel experiments in mice carrying a mutation that delays Wallerian degeneration of synapses (WldS), in which reinnervation is also delayed, and use genetically modified mice that exhibit enhanced regenerative sprouting and bona fide long-tract regeneration (lines of mice that lack Nogo) to precisely define the relationship between CST regeneration recovery of motor function below the level of the injury. Together, these studies will provide a critical data base regarding the growth capacity of cortico-spinal tract axons in mice, which will be essential for future studies involving genetically modified mice. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS047718-04S1
Application #
7645231
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2005-08-15
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$31,677
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Gallent, Erin A; Steward, Oswald (2018) Neuronal PTEN deletion in adult cortical neurons triggers progressive growth of cell bodies, dendrites, and axons. Exp Neurol 303:12-28
Gallaher, Zachary R; Steward, Oswald (2018) Modest enhancement of sensory axon regeneration in the sciatic nerve with conditional co-deletion of PTEN and SOCS3 in the dorsal root ganglia of adult mice. Exp Neurol 303:120-133
Willenberg, Rafer; Zukor, Katherine; Liu, Kai et al. (2016) Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock-down. J Comp Neurol 524:2654-76
Gutilla, Erin A; Buyukozturk, Melda M; Steward, Oswald (2016) Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice. Exp Neurol 279:27-39
Blanc, Caroline A; Grist, Jonathan J; Rosen, Hugh et al. (2015) Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination. Am J Pathol 185:2819-32
Willenberg, Rafer; Steward, Oswald (2015) Nonspecific labeling limits the utility of Cre-Lox bred CST-YFP mice for studies of corticospinal tract regeneration. J Comp Neurol 523:2665-82
Danilov, Camelia A; Steward, Oswald (2015) Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice. Exp Neurol 266:147-60
Steward, Oswald; Sharp, Kelli G; Yee, Kelly Matsudaira et al. (2014) Characterization of ectopic colonies that form in widespread areas of the nervous system with neural stem cell transplants into the site of a severe spinal cord injury. J Neurosci 34:14013-21
Sharp, Kelli G; Yee, Kelly Matsudaira; Steward, Oswald (2014) A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury. Exp Neurol 257:186-204
Lewandowski, Gail; Steward, Oswald (2014) AAVshRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J Neurosci 34:9951-62

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