Dopamine Modulates Cell Cycle in the Lateral Ganglionic Eminence

Abstract

Dopamine is a neuromodulator the functions of which in the regulation of complex behaviors such as mood, motivation, and attention are well known. Dopamine appears in the brain early in the embryonic period when none of those behaviors is robust, raising the possibility that dopamine may influence brain development. The effects of dopamine on specific developmental processes such as neurogenesis are not fully characterized. The neostriatum is a dopamine-rich region of the developing and mature brain. If dopamine influenced neurogenesis, the effects would likely be pronounced in the neostriatum. Therefore, we examined whether dopamine influenced neostriatal neurogenesis by influencing the cell cycle of progenitor cells in the lateral ganglionic eminence (LGE), the neuroepithelial precursor of the neostriatum. We show that dopamine arrives in the LGE via the nigrostriatal pathway early in the embryonic period and that neostriatal neurogenesis progresses in a dopamine-rich milieu. Dopamine D1-like receptor activation reduces entry of progenitor cells from the G(1)- to S-phase of the cell cycle, whereas D2-like receptor activation produces the opposite effects by promoting G(1)- to S-phase entry. D1-like effects are prominent in the ventricular zone, and D2-like effects are prominent in the subventricular zone. The overall effects of dopamine on the cell cycle are D1-like effects, most likely because of the preponderance of D1-like binding sites in the embryonic neostriatum. These data reveal a novel developmental role for dopamine and underscore the relevance of dopaminergic signaling in brain development.

Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development

“…This is consistent with earlier reports of high levels of D3R mRNA in the ganglionic eminence illustrated by in situ hybridization methods [6]. In general, expression of dopamine receptor mRNAs in forebrain neuroepithelial regions is consistent with the ability of dopamine or its receptor agonists to modulate cell proliferation [33,36,56,57]. The subventricular zone of the P60 forebrain also expressed all five receptor mRNAs.…”

“…Tyrosine-hydroxylase positive axons enter the mouse basal forebrain by E13 and dorsal forebrain by E14, coincident with increases in dopamine content of these two regions [11,33,36]. D1-like and D2-like receptor binding sites appear in the mouse basal forebrain by E13 [34], at least a day after the appearance of the mRNA. Similar findings were reported earlier by others [42].…”

Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain

“…Each of these receptor families has not only a distinct localization pattern within the CNS but also intracellular signaling pathways, which allow dopamine to exert numerous diverse effects on the cells to which they project. Early in the embryonic period, dopamine 17,18 and its receptors 19,20 are present in the highly proliferative germinal zones of the brain, supporting the hypothesis that dopamine plays a role in neurogenesis during brain development. 20 Dopamine arrives in the forebrain via the nigrostriatal pathway at around embryonic day 13 in the mouse, a timepoint at which tyrosine hydroxylase fibres approach the lateral ventricular border and lie in very close proximity to the proliferating progenitor cells.…”

“…20 Dopamine arrives in the forebrain via the nigrostriatal pathway at around embryonic day 13 in the mouse, a timepoint at which tyrosine hydroxylase fibres approach the lateral ventricular border and lie in very close proximity to the proliferating progenitor cells. 17 The onset of dopaminergic innervation to this area coincides with changes in progenitor cell proliferation, with dopamine D1 receptor activation seeming to reduce the entry of progenitor cells from the G 1 -to-S phase of the cell cycle, whereas D2 receptor activation promotes G 1 -to-S phase entry and thereby drives proliferation. 17 Thus, the relative abundance of dopaminergic receptors on precursor cells regulates the overall proliferative influence of dopamine on in the number of BrdU-labelled cells (***p < 0.001) (Fig.…”

“…17 The onset of dopaminergic innervation to this area coincides with changes in progenitor cell proliferation, with dopamine D1 receptor activation seeming to reduce the entry of progenitor cells from the G 1 -to-S phase of the cell cycle, whereas D2 receptor activation promotes G 1 -to-S phase entry and thereby drives proliferation. 17 Thus, the relative abundance of dopaminergic receptors on precursor cells regulates the overall proliferative influence of dopamine on in the number of BrdU-labelled cells (***p < 0.001) (Fig. 1A and B), demonstrating that this combination of dopamine agonists induces proliferation.…”