We propose to investigate why central visual pathways fail to regenerate after injury and how their repair can be enhanced. We will focus on why retinal ganglion cell axons fail to regenerate after optic nerve injury. Many studies point to multifactorial cause of retinal ganglion cell axon regenerative failure. On the one hand adult retinal ganglion cells have an intrinsically limited axon growth potential. On the other, the optic nerve environment after nerve injury is strongly inhibitory to regenerating axons as a result of inhibitory cues deriving from both degenerating myelin and reactive astrocytes. We do not yet have an in depth understanding of the molecular basis of these phenomena. The proposed experiments address a longstanding central question in the field, which is why degenerating myelin, which is strongly inhibitory to axon regeneration, is cleared robustly by phagocytosis after PNS injury but not after CNS injury. Schwann cells play a critical role in clearning degenerating PNS myelin but the relevant phagocytic pathways are not yet known. We have recently discovered that Schwann cells in the PNS and astrocytes in the CNS express the same repertoire of phagocytic pathways including the Mertk/Axl and the Megf10/LRP1 pathways. This is surprising as only Schwann cells perform robust myelin clearance after nerve injury. Furthermore, we have established that at least one of these pathways, the Mertk pathway, is required for clearance of PNS myelin debris. The proposed experiments are designed to elucidate the molecular mechanisms of Schwann cell-mediated myelin debris clearance and to investigate why these same pathways do not mediate myelin clearance after CNS injury. Using conditional knockout mice, in which each pathway is deleted specifically in Schwann cells, we will test the hypothesis that the Mertk/Axl and Megf10/LRP1 phagocytic pathways are required for glial-mediated clearance of degenerating (inhibitory) PNS myelin. We will then test several hypotheses for why astrocyte phagocytosis of myelin is disabled in the injured optic nerve, either because the required phagocytic pathways are downregulated in astrocytes after optic nerve injury or because degenerating CNS myelin is resistant to glial-mediated phagocytosis. Our ultimate goal is to determine how phagocytic clearance of degenerating myelin can be activated in optic nerve astrocytes in order to develop new treatments to promote retinal ganglion cell axon regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis, and optic neuropathy.

Public Health Relevance

Our goal is to understand why retinal ganglion cells and other CNS axons do not regenerate after injury and how their regeneration can be enhanced. The proposed experiments are designed to test the hypothesis that specific glial phagocytic pathways robustly clear degenerating PNS but not CNS myelin. We will elucidate the relevant phagocytic pathways in Schwann cells, investigate why these same pathways which are present in astrocytes do not phagocytose degenerating CNS myelin, and then test whether more robust glial phagocytosis of degenerating CNS myelin will promote retinal ganglion cell regeneration and optic nerve repair.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Steinmetz, Michael A
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Stanford University
Schools of Medicine
United States
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Mandemakers, Wim (2014) Immunopanning of retrograde-labeled corticospinal motor neurons from early postnatal rodents. Cold Spring Harb Protoc 2014:375-88
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