Download Transcriptional control of midbrain dopaminergic neuronal

Abstract
1. Transcriptional control of midbrain dopaminergic neuron development
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, Pitx3, a homeodomain transcription factor, is thought
to be involved in the development of ventral midbrain DA neurons. Our recent work showed that
Pitx3 is the first known transcription factor that critically and selectively controls proper
development of A9 DA neurons and the nigrostriatal pathway. This observation is of great
importance to further understand the mechanism(s) of DA neuron development and may offer an
avenue to better understand the mechanism of selective degeneration of A9 DA neurons in
Parkinson’s disease. Our further study demonstrated that Pitx3-deficient aphakia (ak) mice display
motor deficits that are reversed by 3,4-dihydroxyphenylalanine (L-DOPA) as well as evidence of
dopaminergic supersensitivity in the striatum. Thus ak mice represent a novel genetic model
exhibiting important characteristics of a valid animal model of PD to test the efficacy of
therapeutic regimens and to study the functional changes in the striatum following dopamine
depletion and subsequent L-DOPA treatment.
2. Subneuron-specific gene expression in the brain
Genetic modification of a specific neuronal group is a prerequisite both to gain information about
involvement of the neuronal group in a certain brain function and to develop effective gene therapy
regimens for brain diseases caused by dysfunction of the neuronal group. To accomplish subneuronspecific gene modification, our efforts have been centered on the development of novel promoter systems
driving gene expression exclusively in a specific neuronal cell type. By devising two unique methods
termed "multimerization" and "optimization", we have successfully developed promoters that target the
noradrenergic neuronal group efficiently. Since noradrenergic neurons are at the center of many important
brain functions and abnormal function of these neurons is implicated in major brain disorders including
depression and drug addiction, the novel noradrenergic-specific gene expression systems offer the
possibility to investigate and eventually to treat these brain diseases. Furthermore, the strategies developed
in our study can be also applied to generate gene promoter systems that target other types of neurons or
cells.