Growth factor function in the development and maintenance of midbrain dopaminergic neurons: concepts, facts and...

Dopaminergic neurons of the nigrostriatal system are important in the control of motor performance and degenerate in Parkinson's disease. Therefore, in order to design novel strategies for the treatment of Parkinson's disease, it is important for us to understand their development, function, trophic factor requirements, plasticity and susceptibility to toxic influences. A large and still increasing number of growth factors have been implicated in the regulation of the survival and differentiation of dopaminergic neurons. These factors may also protect against a variety of toxic influences. On the basis of their localization, putative sources and mechanisms of actions, such growth factors fall into several categories: (i) local factors within the midbrain influencing proliferation, transmitter phenotype, migration, positioning and neurite growth of stem cells and early neurons; (ii) factors acting retrogradely from the striatum, which are responsible for intrastriatal sprouting and navigation of newly arrived axons as well as life-long maintenance of the dopaminergic nigrostriatal connection; (iii) factors coming into play when the system is toxically impaired; (iv) factors directly acting on dopaminergic neurons; and (v) factors provided by cytokinestimulated astroglia, microglia and neurons affecting dopaminergic neurons anterogradely. This article reviews actions of growth factors on dopaminergic neurons in vitro and in vivo, with a focus on members of the transforming growth factor (TGF)-beta superfamily. TGF-beta s may be particularly relevant to dopaminergic neurons, since they are expressed in the nigrostriatal system from early embryonic stages to adulthood and are significantly up-regulated in response to lesions.