Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice

Abstract

Dopaminergic (DA) neurons in the ventral midbrain nuclei, substantia nigra pars compacta (SNc, A9) and ventral tegmental area (VTA, A10), play important roles in the control of movement, emotion, cognition, and reward related behavior. Although several transcription factors have been shown to be critical for midbrain DA neuron development, there has been no report of factor(s) that differentially regulate individual DA neuronal groups. Based on its highly restricted expression in the SNc and VTA in the brain, we hypothesize that the homeobox transcription factor Pitx3 may critically regulate the development of ventral midbrain DA neurons. In this study, we report that in Pitx3-deficient ak/ak mice, DA neurons in the SNc and the nigrostriatal pathway fail to develop properly, and DA levels are reduced to 10% of the wild type mice in the dorsal striatum. On the contrary, A10 neurons are intact in ak/ak mice and DA levels within their projection areas are not affected. This region-specific defect was already evident in newborn mice, suggesting that the defect had occurred during the early stages of mouse development. Taken together, our results indicate that Pitx3 is the first known transcription factor that may critically and selectively control proper development of A9 DA neurons and the nigrostriatal pathway. This observation is of great importance in understanding the mechanisms of DA neuron development and may also help us to understand the mechanism of selective degeneration of A9 DA neurons in Parkinson’s disease and to devise novel therapeutic approaches for the disorder.