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...