ADAPTATION OF NEURONS TO INHIBITORY EXTRACELLULAR MATRIX

University Of Utah, Salt Lake City UT

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Abstract

The adult central nervous system (CNS) does not readily support axonal regeneration following injury. In contrast, there is extensive regeneration and functional recovery in embryos following CNS damage. The inability of the adult CNS to regenerate appears to be due both to changes in the extracellular environment of the nervous system that did make it less permissive to neuronal growth and to changes in the intrinsic ability of adult neurons to regenerate damage axons. By the end of embryonic development, the expressions of growth-promoting or stimulatory extracellular matrix molecules in the CNS is quite low. Myelin-associated factors found in mature brain tissue actively inhibit axonal growth and following injury, several additional inhibitory proteins are up-regulated in regions of scarring. Compounds these less than ideal extracellular conditions, the regeneration of adult neurons is somehow compromised by changes associated with neuronal maturation. Recent work has shown that embryonic neurons readily adapt both to low availability of growth promoting molecules and to the presence of inhibitory compounds by regulating the expression of integrins--the receptors extracellular matrix proteins that mediate axon extension. The compensatory regulation of integrin by components of the matrix has not been previous described for any cell type, may contribute to the superior regenerative performance of embryonic neurons under less than ideal extracellular conditions. Integrins are known to interact with both extracellular and cytoskeletal proteins. In Aim 1, the contributions of ligand and cytoskeletal binding to the regulation of integrin expression will be examined using antibodies, pharmacological reagents and integrin mutant constructs. The contribution of integrin regulation to the adaptation of embryonic neurons to inhibitory matrix components will be characterized in Aim 2. Neuronal response to members of two major inhibitory families that are expressed in the CNS following injury will be determined. The role of one inhibitory proteoglycan (aggrecan) in neuronal development will be examined using mutant animals that do not express aggrecan. Experiments proposed in Aims 3 and 4 will determine whether increased integrin expression is sufficient to mediate neuronal adaptation to both low availability of ligand and to inhibitory molecules (conditions similar to those in the adult CNS following injury). Integrin expression will be increased in both embryonic and adult neurons using replication- deficient adenoviral constructs. The performance of neurons with increased integrin expression will be examined on substrata that would otherwise not support neuronal growth. In summary, these experiments will greatly strengthen our understanding of two novel forms of integrin regulation, and potentially provide a basis for improving the regenerative performance of adult neurons.