Protein F1/GAP-43 is a protein kinase C substrate associated with axonal growth and synaptic plasticity. We used in situ hybridization in rat brain to determine the cellular distribution of its gene expression. Throughout the septotemporal axis of the adult hippocampus, pyramidal cells express F1/GAP-43 mRNA, but granule cells do not. To determine if F1/GAP-43 expression in granule cells ever occurs, we studied its expression in development during mossy fiber outgrowth, when expression should be maximal. Quantitation of relative hybridization levels in the hippocampus revealed a modest increase in granule cell F1/GAP-43 mRNA coincident with mossy fiber outgrowth. But even the peak hybridization in granule cells on day 16 was 75% less than in pyramidal cells. The distribution of grains was over the entire granule cell layer at day 9, but was restricted by day 20 to the inner aspect of the layer, the site of the youngest cells which are still sending out axonal processes. Cell-selective expression of F1/GAP-43 within a particular brain structure was not restricted to the hippocampus. In cerebellum, F1/GAP-43 hybridization was detected in granule cells but not Purkinje cells; in olfactory bulb, mitral cells but not internal granule cells; in habenula, cells in the lateral but not medial nucleus; in substantia nigra, pars compacta cells but not cells in pars reticulata. Neurons containing biogenic amines exhibited intense F1/GAP-43 hybridization: substantia nigra pars compacta (dopamine), the locus coeruleus (norepinephrine), and dorsal raphe (serotonin). In contrast, cholinergic neurons exhibited little (basal forebrain) or no (medial habenula) hybridization. F1/GAP-43 expression is not restricted to a specific cell type and is not correlated with axon length. High F1/GAP-43 expression is apparent in many neurons having either neuromodulatory or memory storage functions. We propose that F1/GAP-43 is important for accelerating process outgrowth and synaptic remodeling, rather than directing growth itself.