Degeneration of nigrostriatal dopaminergic system is the principal lesion in
Parkinson's disease. Because
glial cell line-derived neurotrophic factor (
GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of
GDNF has been attempted for
Parkinson's disease treatment but with variable success. For improving
GDNF-based
therapies, knowledge on physiological role of endogenous
GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of
Gdnf 3'UTR in
Gdnf endogenous locus yields
GDNF hypermorphic mice with increased, but spatially unchanged
GDNF expression, enabling analysis of postnatal
GDNF function. We found that increased level of
GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level,
GDNF levels increased striatal tissue
dopamine levels and augmented striatal
dopamine release and re-uptake. In a
proteasome inhibitor lactacystin-induced model of
Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal
dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated
GDNF applications were not observed. Enhanced
GDNF levels up-regulated striatal
dopamine transporter activity by at least five fold resulting in enhanced susceptibility to
6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how
GDNF levels regulate kidney development and identify
microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of
GDNF expression via interaction with
Gdnf 3'UTR in vitro. Our results reveal the role of
GDNF in nigrostriatal
dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of
GDNF. Furthermore, our results suggest that
3'UTR targeting may constitute a useful tool in analyzing gene function.