STATEMENT
Work in my laboratory is directed at the role of neuronal growth factors in the development and regeneration of axons. We employ sensory neurons of the DRG as a model system. Sensory neurons are unique in elaborating a peripheral axon that regenerates readily after injury and a central axon projecting in the spinal cord that does not. This work is directly relevant to a major NINDS goal of achieving spinal cord repair. We are pursuing 3 important aspects of axon growth regulation by neurotrophins:

Neurotrophin signaling mediators in the development of axon projections: DRG neurons are powerfully regulated by members of the NGF and GDNF families of neuronal growth factors. We have recently defined critical functions for NGF and NT3 in the development of DRG peripheral and central projections (Neuron 25: 345–357; Neuron 38: 403-416). We have also recently shown critical but separable functions for Raf/Erk and PI3K signaling during sensory axon growth in vitro (Neuron 35: 65-76). A major difficulty in this field has been that signaling mediator mutants are embryonic or early postnatal lethal due to abnormalities in development of multiple organs. We have now generated conditional mutant mice where Raf signaling has been abolished first only in the nervous system and second only in DRG neurons. These mice have striking neurodevelopmental abnormalities. The development of peripheral and central DRG axon projections in these animals is under active investigation.

Snider Lab Group

Neurotrophin signaling and the axon cytoskeleton: In addition to roles in regulating gene transcription, we can expect that neurotrophin signaling mediators will have powerful local actions on the axon cytoskeleton. Using immunolabeling of phosphorylated signaling mediators and real time visualization of GFP-fusion proteins at the growth cone, we are exploring the role of localized PI3 kinase signaling in cytoskeletal regulation. This spatially activated PI3K signaling is conveyed downstream through a localized inactivation of glycogen synthase kinase 3? (GSK-3?). These two spatially coupled kinases control axon growth via regulation of a microtubule plus end binding protein, adenomatous polyposis coli (APC). Our results demonstrate that NGF signals are transduced to the axon cytoskeleton via activation of a conserved cell polarity signaling pathway (Neuron 42: 897 – 912).

Mouse genetic studies of axon regeneration: Neurotrophins have powerful pharmacologic effects on axon growth in adult animals. We have recently identified a pathway downstream of both neurotrophin and integrin signaling that mediates axon assembly after peripheral axotomy (Zhou et al., submitted). Nothing is known about the role of these signaling mediators in axon regeneration, because of early death of mutant mice. Inducible null mutations specific to DRG neurons will be required for this analysis. We have generated an inducible DRG specific Cre line for crossing with floxed allele lines in studies of axon regeneration.


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