Table 1. Summary of GDNF functions identified using GDNF hypermorphic mice.

The main findings of this study are reported in comparison with published reports from ectopic GDNF applications and GDNF knock-out mice. The forth column indicates whether the observations made in GDNF hypermorphic mice are consistent with function predicted from ectopic GDNF applications and from Gdnf gene deletion studies, expand the previous knowledge or provide novel information.

Endogenous GDNF elevation (this study)	Reported ectopic GDNF expression or gene knock-out approaches		Novelty of the finding
Observed phenotype	Observed phenotype	Approach
Increased motor activity upon amphetamine injection	Increased motor activity upon amphetamine injection	Nigrostriatal recombinant GDNF injection and viral gene delivery [5,26]	Consistent with ectopic/KO approaches
GDNF controls DA cell number at P7.5	GDNF controls DA cell number at P7.5	2–3 fold transgenic over-expression of GDNF in the forebrain using CaMKIIα promoter [8]	Consistent with ectopic/KO approaches
Striatal DA levels are maintained upon supra-nigral lactacystin injection	Striatal DA levels are maintained upon supra-nigral lactacystin injection	Striatal viral gene delivery [39]	Consistent with ectopic/KO approaches
Increased stimulated and amphetamine -induced DA release	Increased stimulated and amphetamine -induced DA release	Intranigral GDNF protein injection [27,28]	Consistent with ectopic/KO approaches
GDNF levels regulate kidney size and morphological maturation	GDNF is required for the induction of the ureteric bud development during early embryogenesis	GDNF gene deletion [15]	Consistent and expanding ectopic/KO approaches
Elevated GDNF increases the number of DA neurons and enhances DA system functionduring development and in adulthood	GDNF deletion or reduction has no effect on the number of DA neurons in adulthood and upon aging; no gross effect on animal behavior	Conditional GDNF deletion or reduction using three Cre lines [10]	Novel
Elevated GDNF increases the number of DA neurons during development which is retained in adulthood.	Elevated GDNF does not increase the number of DA neurons after two weeks of age	2–3 fold transgenic over-expression of GDNF in the forebrain using CaMKIIα promoter [8]	Novel
Elevated GDNF increases striatal DA release and re-uptake	Elevated GDNF has no effect on DA release and re-uptake	2–3 fold transgenic over-expression of GDNF in the forebrain using CaMKIIα promoter [8]	Novel
No effect on food intake and bodyweight at least until 3–4 months of age	Reduction in food intake and weight loss within 1–2 weeks after GDNF overexpression	Nigrostriatal recombinant GDNF injection and viral gene delivery [6,26]	Novel
No effect on striatal tyrosine hydroxylase levels at least until 3 months of age	Downregulation of striatal tyrosine hydroxylase levels after 6 weeks	Nigrostriatal viral gene delivery [5,30]	Novel
No effect on spontaneous motor activity	Spontaneous motor hyperactivity	Nigrostriatal recombinant GDNF injection [26–29]	Novel
Elevation in total striatal DA levels	; No effect on total striatal DA levels; elevation in DA turnover	Nigrostriatal recombinant GDNF injection and viral gene delivery [5,26,28]	Novel
No aberrant sprouting of DA fibers	Sprouting of DA fibers towards GDNF injection site	Nigrostriatal recombinant GDNF injection and viral gene delivery [4,26,40]	Novel
Elevated GDNF augments DA concentration -dependent increase in DAT activity	Not addressed previously		Novel