During development, mammalian neurons can extend long axonal process, but with maturation, lose the capacity to express this growth within the central nervous system (CNS). Consequently, when severed, adult CNS axons fail to regenerate resulting in permanent dysfunction. Most recent work has focused on the possibility that glia mature so as to prevent the regeneration of CNS axons. In contrast, these proposed studies will explore the possibility that neurons themselves mature so as to become unable to grow within the CNS environment even though they retain considerable intrinsic capacity for growth. This possibility is supported by preliminary evidence showing that with maturation axons undergo several functional and molecular changes that likely compromise their ability to grow within a glial environment. - The proposed studies make extensive use of the in vitro retinal explant system developed in this laboratory to elicit regenerative growth of adult optic axons in tissue culture. This system will be used to compare the cellular function and molecular constitution of regenerating adult optic axons with growing embryonic axons. Three areas relevant to regeneration will be investigated. The first is cell surface molecules involved in the regulation neurite growth on astrocytes. Specifically, the presence and function of integrins, N-cadherin, N-CAM and Thy-1 will be compared in adult and embryonic optic fibers. The second area is intracellular molecules that are associated with and thought to be required for axons growth. One in particular, GAP-43, will be assayed for its expression in adult axons and for possible down-regulation by glia. The third area is cellular interactions between optic fibers and glia. The possibility will be tested that adult optic axons, in marked contrast to embryonic axons, are deficient in their ability to grow over astroglia in culture. Initial characterization of the basis of this differential interaction will be explored. These studies will identify differences between adult and embryonic growing axons that are important for understanding regenerative failure in the adult CNS and for developing future therapies for promoting axonal regeneration.
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