Axonally transported proteins associated with axon growth in rabbit central and peripheral nervous systems

Abstract

In an effort to determine whether the "growth state" and the "mature state" of a neuron are differentiated by different programs of gene expression, we have compared the rapidly transported (group I) proteins in growing and nongrowing axons in rabbits . We observed two polypeptides (GAP-23 and GAP-43) which were of particular interest because of their apparent association with axon growth . GAP-43 was rapidly transported in the central nervous system (CNS) (retinal ganglion cell) axons of neonatal animals, but its relative amount declined precipitously with subsequent development. It could not be reinduced by axotomy of the adult optic nerves, which do not regenerate ; however, it was induced after axotomy of an adult peripheral nervous system nerve (the hypoglossal nerve, which does regenerate) which transported only very low levels of GAP-43 before axotomy. The second polypeptide, GAP-23 followed the same pattern of growth-associated transport, except that it was transported at significant levels in uninjured adult hypoglossal nerves and not further induced by axotomy. These observations are consistent with the "GAP hypothesis" that the neuronal growth state can be defined as an altered program of gene expression exemplified in part by the expression of GAP genes whose products are involved in critical growth-specific functions. When interpreted in terms of the GAP hypothesis, they lead to the following conclusions: (a) the growth state can be subdivided into a "synaptogenic state" characterized by the transport of GAP-23 but not GAP-43, and an "axon elongation state" requiring both GAPS; (b) with respect to the expression of GAP genes, regeneration involves a recapitulation of a neonatal state of the neuron ; and (c) the failure of mammalian CNS neurons to express the GAP genes may underly the failure of CNS axons to regenerate after axon injury .Certain rapidly transported proteins (which we have designated "growth-associated polypeptides" [GAPs]) are specifically induced during the regeneration of amphibian retinal ganglion cell axons (17). In the preceding paper we proposed that the GAPs are proteins involved in key functions related to axon growth and that their induction is a critical event in axon regeneration. The mammalian nervous system provides a particularly interesting and important system in which to further evaluate this hypothesis, because it is possible to distinguish between metabolic changes resulting from axon injury itself and those directly related to axon growth : mature neurons of the mammalian peripheral nervous system (PNS) (e.g., the hypoglossal and vagus nerves) retain the ability to regenerate their axons after injury, while those of the central nervous system (CNS) (e.g., the optic nerve and spinal cord) generally do not . The failure of CNS regeneration is an important clinical problem and in the past has been explained in terms of models emphasizing either extrinsic or intrinsic factors . A particularly durable extrinsic model has been that regenerating CNS axons are ph...

A Role for Nitric Oxide in the Development of the Ferret Retinogeniculate Projection

“…A possible mode of action with respect to ADPRT is that it acts on growth-associated protein 43 (GAP-43; Coggins et al, 1993;cf. Luo and Vallano, 1995); this protein is expressed in growing axons during development and regeneration (Skene and Willard, 1981;Meiri et al, 1988;Moya et al, 1988) and may have a role in remodeling synaptic connections (Erzurumlu et al, 1990; for review, see Benowitz and Routtenberg, 1987). Another possibility suggested by a study of cultured dorsal root ganglia (Hess et al, 1993) is that NO inhibits growth cone elongation by inhibiting palmitoylation of proteins such as GAP-43 and SNAP-25; this effect is independent of guanylyl cyclase.…”

Lens Injury Stimulates Axon Regeneration in the Mature Rat Optic Nerve

“…Developmentally, RGCs express this protein during axon outgrowth and synaptic refinement, then downregulate it as their connections mature (Skene and Willard, 1981b;Meiri et al, 1986;Moya et al, 1988). Normally, GAP-43 is transiently upregulated after axotomy and declines as RGCs undergo atrophic changes (Doster et al, 1991;Fournier et al, 1997;Wodarczyk et al, 1997;Wouters et al, 1998).…”

Ligand-induced growth cone collapse: amplification and blockade by variant GAP-43 peptides

“…It is enriched in most, if not all, growth cones during development and in adult CNS regions notable for their "plasticity" (Benowitz et al, 1988). It has been speculated to be necessary for axon elongation (Skene and Willard, 1981), growth cone shape (Zuber et al, 1989a), and neurotransmission (Dekker et al, 1989), as well as for signal transduction at the growth cone or synapse . GAP-43 has several defined biochemical functions as an isolated protein.…”

“…Its pattern of expression in developing (de la Monte et al, 1989), regenerating (Skene and Willard, 1981), and remodeling (Benowitz et al, 1988) neurons has led to speculation that it is related to neuronal growth and plasticity. When introduced into non-neural cells, it certainly can enhance certain surface features of the membrane, such as filopodial extension (Zuber et al, 1989a;Nielander et al, 1993;Widmer and Caroni, 1993), but whether it does so by affecting cytoskeletal motors or by altering sensory input from the cell's environment is unknown.…”