Axon Growth and Regeneration
Monday, March 20, 2006
Presented by the Neurodegenerative Diseases Discussion Group
Organizer: Marie Filbin, Hunter College, CUNY
The Neurodegenerative Diseases Discussion Group focuses broadly on the theme of neurodegenerative diseases in an interdisciplinary fashion. Meetings cover a single issue as it relates to neurodegenerative diseases in general, including cell death, mitochondrial function, protein misfolding, glial cell function, motor neuron deficiencies, and synaptic integrity. In addition, each meeting will feature talks covering basic, clinical, and translational aspects of research into neurodegenerative diseases.
Stephen Strittmatter, Yale University, "Nogo Receptor in Adult CNS Plasticity and Regeneration."
Glenn Yiu, Harvard Medical School, "Signaling Mechanisms Preventing Axon Regeneration in the Adult CNS."
Christopher Henderson, Columbia University, "Intrinsic and Extrinsic Control of Axonal Growth."
"Nogo Receptor in Adult CNS Plasticity and Regeneration"
The failure of adult CMS axons to sprout and to grow after injury limits recovery in a broad range of neurological conditions, including spinal cord injury (SCI), stroke, and neurodegeneration. Significant progress has been achieved towards defining the molecular pathways limiting adult CMS axon growth and towards translating this knowledge into therapeutic opportunities. We identified the Nogo-66 Receptor (NgR) protein as a ligand-binding receptor for the myelin-derived proteins, Nogo and MAG. Pharmacological perturbation of NgR function or genetic disruption of the NgR locus allows an enhanced degree of axonal growth for certain fibers in the post-SCI and post-stroke nervous system. We showed that such CNS fiber growth is associated with improved behavioral recovery of motor function. Success in promoting recovery from injury led us to consider of the physiological rather than pathological role of myelin inhibitors. We found that experience-dependent cortical plasticity is gated by NgR-dependent mechanisms in the absence of injury. While this work has defined one pathway regulating adult CNS axonal sprouting, it has also framed crucial questions about NgR function with regard to specificity of action, spatial distribution, temporal necessity and behavioral role in the uninjured brain.
"Signaling Mechanisms Preventing Axon Regeneration in the Adult CNS"
A major obstacle for successful axon regeneration in the adult central nervous system may be attributed to the non-permissive environment of the mature CNS, including proteoglycans associated with glial scarring (CSPGs), as well as inhibitory molecules in CNS myelin such as Nogo-A, MAG, and OMgp. All three major myelin inhibitors interact with a common receptor complex consisting of the Nogo-66 receptor (NgR), p75 and LINGO-1. Downstream signals such as RhoA can then lead to subsequent stabilization of the actin cytoskeleton to prevent axon regrowth. Yet, while the apparent convergence of these inhibitory signals offers the promise of a single target for developing treatment strategies for clinical use, applications to in vivo injury models have met with limited success, hinting at the complexity of the inhibitory mechanisms that remain unclear to date. For example, while NgR and LINGO-1 are expressed widely across the adult CNS, p75 is absent in most populations of mature neurons. Our studies revealed a novel TNF-R family member, TROY, which can act as a functional homologue of p75. The fact that both p75 and TROY are TNF-R members also led us to discover a significant role of JNK as another downstream mediator of NgR signals. Finally, by screening compound libraries for small molecules that can neutralize the inhibitory activities of either myelin or CSPGs, we found surprising new roles for PKC and EGFR in these inhibitory pathways. Together, our studies unveil a new level of co