MOLECULAR ANATOMY OF THE DEVELOPMENT OF THE HUMAN SUBSTANTIA-NIGRA

A series of 15 fetal and perinatal human brains (from week 12 of fetal life to day 2 after birth) was studied in order to describe the anato mical and molecular correlates of the substantia nigra ontogeny. In si tu hybridization, Immunohistochemistry and binding studies were used t o detect D-2 dopamine receptor (D2R) mRNA, D2R binding sites, dopamine membrane transporter (DAT) mRNA, tyrosine hydroxylase (TH) protein, D -1 dopamine receptor (D1R) protein and D1R binding sites. Dopaminergic (DA) neurons of the substantia nigra were detected through TH immunor eactivity from week 12. At week 16, the substantia nigra was clearly d elineated as a compact group of intermingled neurons and fibers. From week 19, groups of DA neurons mere segregated from the pars reticulata . These groups have been divided into the substantia nigra pars compac ta, the ventral tegmental area and the retrorubral area. The DA neuron s exhibited a gradual increase in size and branching development until bir th. From week 12 onward they expressed several other markers of d opamine transmission, i.e., D2R mRNA, D2R binding sites and DAT mRNA. The ventral tegmental area expressed lower levels of mRNA for DAT and D2R than the pars compacta. From week 12, D1R immunoreactivity and D1R binding sites mere also present in the substantia nigra pars reticula ta. This suggests that projecting striatonigral neurons, known to expr ess the D1R gene, have developed pathways connecting with the substant ia nigra by week 12. Our results demonstrate that the developing subst antia nigra in human displays early transcriptional and translational activity for the main constituents of dopaminergic transmission from w eek 12 and receives at this time dopaminoceptive inputs bearing D1 rec eptors from the striatum. (C) 1997 Wiley-Liss, Inc.