Growth cones are specialized structures that form the distal tips of growing axons. During both normal development of the nervous system and regeneration of injured nerves, growth cones are essential for elongation and guidance of growing axons. Developmental and regenerative axon growth is frequently accompanied by elevated synthesis of a protein designated GAP-43. GAP-43 has now been found to be a major component of growth-cone membranes in developing rat brains. Relative to total protein, GAP-43 is approximately 12 times as abundant in growth-cone membranes as in synaptic membranes from adult brains. Immunohistochemical localization of GAP-43 in frozen sections of developing brain indicates that the protein is specifically associated with neuropil areas containing growth cones and immature synaptic terminals. The results support the proposal that GAP-43 plays a role in axon growth.

Nerve trauma initiates significant changes in the composition of proteins secreted by nonneuronal cells. The most prominent of these proteins is a 37-kDa protein, whose expression correlates with the time course of nerve development, degeneration, and regeneration. We now report that the 37-kfla protein is apolipoprotein E (apoE). We produced a specific antiserum against the 37-kDa protein isolated from previously crushed nerves. This antiserum recognizes a 36-kDa protein in rat serum that we have purified and identified as apoE. The anti-37-kDa antiserum also recognizes apoE on electrophoretic transfer blots of authentic samples of high and very low density lipoproteins. The nerve 37-kDa protein comigrates with apoE by two-dimensional electrophoresis, shares a similar amino acid composition, and reacts with an antiserum against authentic apoE. The purified apoE specifically blocks the immunoprecipitation of [35S~methionine-labeled 37-kDa protein synthesized by nonneuronal cells. Thus, on the basis of its molecular mass, isoelectric point, amino acid composition, and immunological properties, we conclude that the 37-kDa protein is apoE. We also used light microscopic immunohistochemistry to localize apoE following nerve n'jury. In rats with optic nerve lesions, the 37-kDa antiserum bound specifically to the degenerating optic tracts and to the retinorecipient layers of the lateral geniculate nucleus and the superior colliculus. We propose that apoE is synthesized by phagocytic cells in response to nerve injury for the purpose of mobilizing lipids produced as a consequence of axon degeneration.Nonneuronal cells in the mammalian nervous system are estimated to outnumber neurons by 10:1 and may account for nearly half of the volume of the brain (1). Although the functions of some nonneuronal cells [which include astrocytes, oligodendrocytes, and microglia in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS)] are beginning to be understood, thus far little is known at the molecular level of the roles such cells play in the development and in the normal functioning of the nervous system or in response to injury. Recently, it has been shown that nonneuronal cells in the PNS and CNS release soluble proteins into their microenvironment during development (2-4) and following nerve injury (3-5). The fact that the synthesis and secretion of some of these proteins is significantly enhanced during nerve regeneration in the PNS leads naturally to the hypothesis that they may play an important role in determining the ability of an axon to regenerate following injury. The poor regenerative response of most CNS neurons in higher vertebrates might be related to the failure of CNS nonneuronal cells to secrete the requisite proteins necessary for regeneration or the failure to secrete them in sufficient amounts. These considerations serve to emphasize the importance of identifying and characterizing the proteins released by nonneuronal cells in the PNS and CNS and of elucidating how t...

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