Developmental regulation of the serotonergic transmitter phenotype in rostral and caudal raphe neurons by transforming growth factor-beta s

Serotonergic (5-MT) neurons of the CNS develop as two separate clusters, a rostral and a caudal group, within the brain stem raphe, We show here that the transforming growth factors -beta 2 and -beta 3 (TGF-beta) and the TGF- beta type II receptor are expressed in the embryonic rat raphe, when 5-HT n eurons develop and differentiate. To investigate putative roles of TGF-beta s in the regulation of 5-HT neuron development we have generated serum-fre e cultures isolated either from the rostral or the caudal embryonic rat rap he, respectively. In cultures from the caudal E14 raphe saturating concentr ations (5 ng/ml) of TGF-beta 2 and -beta 3 augmented numbers of tryptophan hydroxylase (TpOH) -immunoreactive neurons and cells specifically taking up 5,7-dihydroxytryptamine (5,7-DHT) by about 1.7-fold over a period of 4 day s. Treatment with TGF-beta s also increased uptake of H-3-5HT uptake about 1.7-fold, Alterations in 5-HT neuron numbers were due to the induction of s erotonergic markers rather than increased survival, as shown by the efficac y of delayed short-term treatments. Comparing rostral and caudal raphe cult ures from different embryonic ages suggests that distinct effects of TGF-be ta s reflect the responsiveness of 5-HT neurons at different ages rather th an of different origins. (C) 1999 Wiley-Liss, Inc.