Transforming growth factor-ßs (TGF-ßs) constitute a superfamily of multifunctional cytokines with important implications in morphogenesis, cell differentiation, and tissue remodeling. In the developing nervous system, TGF-ß2 and -ß3 occur in radial and astroglial cells as well as in many populations of postmitotic, differentiating neurons. TGF-ß1 is restricted to the choroid plexus and meninges. In addition to functions related to glial cell maturation and performances, TGF-ß2 and -ß3 are important regulators of neuron survival. In contrast to neurotrophic factors, as for example, neurotrophins, TGF-ßs are most likely not neurotrophic by themselves. However, they can dramatically increase the potency of select neurotrophins, fibroblast growth factor-2, ciliary neurotrophic factor, and glial cell line-derived neurotrophic factor (GDNF). In the case of GDNF, we have shown that GDNF fails to promote the survival of highly purified neuron populations in vitro unless it is supplemented with TGF-ß. This also applies to the in vivo situation, where antibodies to all three TGF-ß isoforms fully prevent the trophic effect of GDNF on axotomized, target-deprived neurons. In addition to the TGF-ß isoforms -ß2 and -ß3, other members of the TGF-ß superfamily are expressed in the nervous system having important roles in embryonic patterning, cell migration, and neuronal transmitter determination. We have cloned and expressed a novel TGF-ß, named growth/differentiation factor-15 (GDF-15). GDF-15 is synthesized in the choroid plexus and released into the CSF, but also occurs in all regions investigated of the developing and adult brain. GDF- 15 is a potent trophic factor for developing and 6-OHDA-lesioned midbrain dopaminergic neurons in vitro and in vivo, matching the potency of GDNF. © 2002 Elsevier Science Ltd. All rights reserved.