NEURTURIN EXERTS POTENT ACTIONS ON SURVIVAL AND FUNCTION OF MIDBRAIN DOPAMINERGIC-NEURONS

Glial cell line-derived neurotrophic factor (GDNF) exhibits potent eff ects on survival and function of midbrain dopaminergic (DA) neurons in a variety of models. Although other growth factors expressed in the v icinity of developing DA neurons have been reported to support surviva l of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neur turin (NTN), a homolog of GDNF, is expressed in the nigrostriatal syst em, and that NTN exerts potent effects on survival and function of mid brain DA neurons. Our findings indicate that NTN mRNA is sequentially expressed in the ventral midbrain and striatum during development and that NTN exhibits survival-promoting actions on both developing and ma ture DA neurons. In vitro, NTN supports survival of embryonic DA neuro ns, and in vivo, direct injection of NTN into the substantia nigra pro tects mature DA neurons from cell death induced by 6-OHDA. Furthermore , administration of NTN into the striatum of intact adult animals indu ces behavioral and biochemical changes associated with functional upre gulation of nigral DA neurons. The similarity in potency and efficacy of NTN and GDNF on DA neurons in several paradigms stands in contrast to the differential distribution of the receptor components GDNF Famil y Receptor alpha 1 (GFR alpha 1) and GFR alpha 2 within the ventral me sencephalon. These results suggest that NTN is an endogenous trophic f actor for midbrain DA neurons and point to the possibility that GDNF a nd NTN may exert redundant trophic influences on nigral DA neurons act ing via a receptor complex that includes GFR alpha 1.