Activin as a neurodifferentiation factor. Our studies of neurotransmitter expression have focused on the expression of neuropeptide transmitters in the avian ciliary ganglion (CG) and have examined the influence of choroidal vascular smooth muscle cells in regulating the differential expression of somatostatin in the CG. In these activities we have identified activin A as a potential target-derived neurodifferentiation factor that can stimulate somatostatin expression in cultured CG neurons. In cultured CG neurons, activin can stimulate the expression of somatostatin in choroid neurons, the pattern of neurotransmitter expression found in vivo, and in the ciliary neurons that would normally not express somatostatin. In vivo, mRNA transcripts of the cActR-IIA appear to be expressed by both choroid and ciliary CG neurons. This suggests that activin might serve as an instructive factor in controlling neuropeptide phenotype. For activin to serve as an instructive factor requires that activin be produced by choroid smooth-muscle target cells. Indeed, activin mRNA and activin-like immunoreactivity are found in choroid cells, in vitro. However, the lack of somatostatin expression by ciliary neurons suggests that activin is not produced by their targets, the iris and ciliary body. This simple view is countered by the observation that activin A mRNA is also present in the iris and activin-like immunoreactivity is detectable in the iris and ciliary body. Instead, the production of the specific activin inhibitor follistatin in the iris and ciliary body is likely to limit the availability of activin to only those neurites innervating the choroid layer, thus accounting for the differential expression of somatostatin in only the choroid CG neurons. This somewhat more complicated arrangement is similar to the mechanism thought to be employed for primary induction during frog embryogenesis. The observations reviewed here are all consistent with the hypothesized role for activin as a molecule whose availability to neurites in the target regulates neurotransmitter expression. Additional in vivo perturbation experiments are needed to further examine this hypothesis; nevertheless, activin appears as a strong candidate for a target-derived neurotransmitter differentiation factor. Activin's potential roles in differentiation: A wide variety of biological effects have been ascribed to activin. Initially identified and purified as a gonadal hormone stimulating the production and release of FSH from the pituitary, activin is also implicated in the stimulation of erythroid differentiation, as a modulator of follicular granulosa cell differentiation, as a mesodermalizing factor in both amphibian and avian early development, and as a component in establishing left-right axial patterning in the chicken embryo. Activin has also been found to be a survival factor for several neuronal cell lines and for rat embryonic neural retina cells in culture. However, activin is not a survival factor for chicken CG neurons in culture. Our observation that activin may play a function in target-derived control of neuropeptide expression adds yet another aspect to the list of its potential biological functions. In addition, activin shares regions of amino acid sequence identity with members of the TGF-beta superfamily, which includes the TGF-betas, Mullerian inhibitory substance, Drosophila decapentaplegic gene product, dorsalin, bone morphogenetic proteins, inhibin, and glial-derived neurotrophic factor. Interestingly, these are all factors that have effects upon cellular differentiation. Effects of activin on other neurons. Activin A--as well as two other TGF-beta superfamily members, BMP-2 and BMP-6--has been shown to induce expression of mRNAs for several neuropeptides in cultured rat sympathetic neurons. In addition, activin A induces ChAT mRNA in cultured sympathetic neurons. (ABSTRACT TRUNCATED)