Induction of a dopaminergic phenotype in cultured striatal neurons by bonemorphogenetic proteins

In the present study, we examined whether the bone morphogenetic proteins ( BMPs), which are important in the developmental specification of transmitte r type in certain classes of neurons, might also play a role in signaling t he differentiation of a dopaminergic (DA) phenotype. We found that BMP-2, - 4 and -6 were each capable of inducing, in a dose and time dependent manner , moderate levels of the DA enzyme tyrosine hydroxylase. (TH) in cultured n eurons from the mouse embryonic striatum. In contradistinction to other TH- inducing agents, BMPs initiated de novo TH expression without the required synergy of exogenous growth factors or co-activating substances and in neur ons presumably aged (E16) beyond the critical period for induction. However , the appearance of TH in induced cells was short-lived (24 h) and could no t be prolonged by repeated supplementation with the BMPs. Inhibitors of the mitogen-activated protein kinase (MAPK/ERK) signaling pathway, PD98059 and apigenin, did not prevent TH induction by BMP-4, as they did other TH indu cing agents, indicating that the MAPK/ERK pathway does not mediate BMPs eff ects on TH expression. We conclude that BMP-2, -4 and -6 can be added to th e expanding inventory of agents capable of inducing TH, making them potenti ally important in the specification of a DA phenotype in stem/precursor cel ls for the treatment of Parkinson's disease. (C) 2001 Elsevier Science BY A ll rights reserved.