Axons in the central nervous system do not regenerate readily after traumatic injury because of the highly inhibitory environment of the adult central nervous system especially following injury. In addition, adult axons generally lack intrinsic growth potential and therefore cannot sustain the initial sprouting observed in some of the injured axons. Furthermore, injured axons often retract further back from where they are lesioned over time, making repair even more challenging. Therefore, combinatorial approaches will be necessary for successful anatomical regeneration and functional recovery. Many axon guidance molecules important in development are still present in the adult central nervous system after the nervous system. Still others are found re- induced after injury. Wnts are guidance cues that control pathfinding of a number of axons along the rostral-caudal axis of the developing spinal cord. Wnts attract ascending axons via their seven-span transmembrane receptors, Frizzleds, and repel others via a different transmembrane receptor, Ryk, in the spinal cord. Our studies showed that the re-induced Wnt signaling system regulates the growth cone of axons in the injured adult central nervous system. Ryk-mediated Wnt repulsion causes the well-known retraction/die back of injured corticospinal tract axons and limits the regenerative potential of proprioceptive sensory axons even after conditioning lesion of their peripheral branches, whereby crushing the peripheral branch enhances the growth state of the central branch of sensory axons. This grant tests whether more effective regeneration can occur by combinatorial approaches. We will test whether combining Wnt signaling manipulation and PTEN deletion can further enhance the regenerative potential of conditioning lesion.

Public Health Relevance

Effective regeneration and recovery require combinatorial approaches to alter both the extrinsic growth environment and intrinsic growth properties of neuronal axons. This grant will test combinatorial approaches to improve regeneration using spinal cord injury models. This study will also benefit patients who need nerve regeneration and repair in general, in addition to spinal cord injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakeman, Lyn B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
Zip Code
Hollis 2nd, Edmund R; Ishiko, Nao; Yu, Ting et al. (2016) Ryk controls remapping of motor cortex during functional recovery after spinal cord injury. Nat Neurosci 19:697-705
Hollis 2nd, Edmund R; Ishiko, Nao; Pessian, Maysam et al. (2015) Remodelling of spared proprioceptive circuit involving a small number of neurons supports functional recovery. Nat Commun 6:6079
Hollis 2nd, Edmund R; Ishiko, Nao; Tolentino, Kristine et al. (2015) A novel and robust conditioning lesion induced by ethidium bromide. Exp Neurol 265:30-9
Lemmon, Vance P; Ferguson, Adam R; Popovich, Phillip G et al. (2014) Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments. J Neurotrauma 31:1354-61
Onishi, Keisuke; Hollis, Edmund; Zou, Yimin (2014) Axon guidance and injury-lessons from Wnts and Wnt signaling. Curr Opin Neurobiol 27:232-40
Zou, Yimin (2013) An update on spinal cord injury research. Neurosci Bull 29:399-401
Hollis 2nd, Edmund R; Zou, Yimin (2012) Reinduced Wnt signaling limits regenerative potential of sensory axons in the spinal cord following conditioning lesion. Proc Natl Acad Sci U S A 109:14663-8
Hollis 2nd, Edmund R; Zou, Yimin (2012) Expression of the Wnt signaling system in central nervous system axon guidance and regeneration. Front Mol Neurosci 5:5