HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch–Nyhan disease

In Lesch–Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that L...

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Published in:	Cellular and molecular life sciences : CMLS Vol. 79; no. 6; p. 341
Main Authors:	Witteveen, J. S., Loopstok, S. R., Ballesteros, L. Luque, Boonstra, A., van Bakel, N. H. M., van Boekel, W. H. P., Martens, G. J. M., Visser, J. E., Kolk, S. M.
Format:	Journal Article
Language:	English
Published:	Cham Springer International Publishing 01-06-2022 Springer Nature B.V
Subjects:	Abnormalities Biochemistry Biomedical and Life Sciences Biomedicine Brain Cell Biology Cell cycle Cell migration Circuits Cognitive ability Dopamine Dopamine receptors Dystonia Embryogenesis Embryonic growth stage Guanine Hypoxanthine Innervation Life Sciences Mesencephalon Molecular modelling Neurodevelopmental disorders Neuronal-glial interactions Neurons Original Original Article Phenotypes Radial glial cells Self-injury Somatosensory cortex Therapeutic applications Substantia nigra (SN) Radial glia Otx2 HPRT1 Sox6 Ventral tegmental area (VTA)
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Summary:	In Lesch–Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH + cells and an abnormal mDA subpopulation organization at E18.5. Finally, dopaminergic innervation was disorganized in prefrontal and decreased in HGprt deficient primary motor and somatosensory cortices. These data provide direct in vivo evidence for a neurodevelopmental nature of the brain disorder in LND. Future studies should not only focus the specific molecular mechanisms underlying the reported neurodevelopmental abnormalities, but also on optimal timing of therapeutic interventions to rescue the DA neuron defects, which may also be relevant for other neurodevelopmental disorders.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-682X 1420-9071
DOI:	10.1007/s00018-022-04326-x