Partial biopterin deficiency disturbs postnatal development of the dopaminergic system in the brain.
Postnatal development of dopaminergic system is closely related to the development of psychomotor function. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of dopamine and requires tetrahydrobiopterin (BH4) as a cofactor. To clarify the effect of partial BH4 deficiency on postnatal development of the dopaminergic system, we examined two lines of mutant mice lacking a BH4-biosynthesizing enzyme, including sepiapterin reductase knock-out (Spr(-/-)) mice and genetically rescued 6-pyruvoyltetrahydropterin synthase knock-out (DPS-Pts(-/-)) mice. We found that biopterin contents in the brains of these knock-out mice were moderately decreased from postnatal day 0 (P0) and remained constant up to P21. In contrast, the effects of BH4 deficiency on dopamine and TH protein levels were more manifested during the postnatal development. Both of dopamine and TH protein levels were greatly increased from P0 to P21 in wild-type mice but not in those mutant mice. Serotonin levels in those mutant mice were also severely suppressed after P7. Moreover, striatal TH immunoreactivity in Spr(-/-) mice showed a drop in the late developmental stage, when those mice exhibited hind-limb clasping behavior, a type of motor dysfunction. Our results demonstrate a critical role of biopterin in the augmentation of TH protein in the postnatal period. The developmental manifestation of psychomotor symptoms in BH4 deficiency might be attributable at least partially to high dependence of dopaminergic development on BH4 availability.
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
Daigo
D
Homma
Chiho
C
Sumi-Ichinose
Hirofumi
H
Tokuoka
Kazuhisa
K
Ikemoto
Takahide
T
Nomura
Kazunao
K
Kondo
Setsuko
S
Katoh
Hiroshi
H
Ichinose
D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000172:deficiency* / Q000378:metabolism; D003342:Corpus Striatum / Q000002:abnormalities* / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010649:Phenylalanine / Q000378:metabolism; D010661:Phenylketonurias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019761:Phosphorus-Oxygen Lyases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D013378:Substantia Nigra / Q000002:abnormalities / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001708:Biopterins; D014443:Tyrosine; D010649:Phenylalanine; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D014446:Tyrosine 3-Monooxygenase; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase; D004298:Dopamine