Genetic control of midbrain dopamine systems

Abstract

The midbrain dopaminergic (mDA) system, organized in the substantia nigra compacta (SNc) and ventral tegmental area (VTA), regulates movement control and behavior as highlighted by the dramatic consequences of its degeneration in Parkinson’s disease and its implications in psychiatric and affective disorders. Therefore, the neurobiology, pharmacology and pathology of the mDA system have been investigated extensively for many years. A neuropathological enigma is posed by the selective degeneration of the SNc dopamine neurons in Parkinson's disease. Apparently, these neurons are selectively vulnerable to degeneration, since dopamine neurons of the VTA are largely spared. Although psychiatric and affective disorders are considered to have a genetic neurodevelopmental origin, little is known about the development of the mDA system and the underlying genetic cascades.

We hypothesize that the difference in vulnerability between mDA neurons of the SNc and those of the VTA roots in the molecular make-up of these neurons, and originates from different differentiation routes during embryonic development. The aim of this thesis was therefore to establish a model for the genetic control regulating development and function of the mDA system and to investigate the role of Pitx3 within this model in relation to other regulatory genes, which together generate molecular cascades leading to the specific mDA phenotype.

Our results suggest that mDA precursor cells undergo a multi-stage differentiation process, regulated in a spatiotemporal manner by specific transcription factors that are expressed during different phases of mDA development. At least two independent cascades are involved in establishing the dopaminergic neurotransmitter identity of mDA neurons. One cascade involves the nuclear hormone receptor Nurr1, required for induction of tyrosine hydroxylase (TH), the vesicular monoamine transporter type 2 (VMAT2) and the dopamine transporter. Another cascade involves a not yet identified factor required for the induction of L-aromatic amino acid decarboxylase (AADC). The homeodomain gene Pitx3 is involved in a neurotransmitter independent cascade essential for the development/survival of mDA neurons specifically located in the SNc. Pitx3-deficient mice display specific molecular and electrophysiological alterations, which may serve an adaptive strategy to compensate for the loss of dopaminergic innervation of the dorsal striatum in order to ensure appropriate in vivo functions of the animal. The position of the presumed mDA precursors in the diencephalon suggests that the neuroepithelial origin of mDA precursors might underlie the molecular mechanisms specifying the specific vulnerability of mDA subsets.

As we start to understand consequences of inactivation of genes that are part of genetic programs involved in mDA development and function, one may speculate on their significance as candidate genes for association with dopamine-related mental disorders on the one hand, and on the other hand as tools to manipulate dopamine neurons in therapies aiming to rescue or replace mDA neurons in Parkinson’s disease. The identification of genes regulated by Pitx3 might open new avenues to unravel these mechanisms and might provide new insights into the selective degeneration of SNc mDA neurons in Parkinson's disease.