Yan, HMC; (2006) Genetic studies into the origin and transcriptional regulation of midbrain dopaminergic neurons in mice. Doctoral thesis , UCL (University College London).

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Abstract

The midbrain dopaminergic (mDA) neurons, consisting of anatomically and functionally heterogeneous cell populations, are the major source of dopamine in the central nervous system. They are involved in diverse psychiatric and neurological disorders, including Parkinson's disease (PD), which is marked by the specific degeneration of mDA neurons in the substantia nigra pars compacta. Therefore, understanding the origin and the development of this specific subpopulation will greatly facilitate the development of cell replacement therapy for PD. Using genetic fate mapping studies, we suggest that mDA neurons originate from the floor plate of midbrain and caudal diencephalon. Unlike the popular believe that the different mDA populations are generated from spatially distinct progenitors, our data have ruled out the medial versus lateral correlation between progenitors and neuronal populations. We provide evidence that medial progenitors can develop into both medial and lateral mDA populations, and late born mDA neurons from lateral progenitors predominantly populate the medial nuclei, suggesting a complex mechanism for the generation of different mDA subpopulations. The LIM-homeodomain transcription factors, Lmxla and Lmxlb, are expressed in both mDA progenitors and neurons. Lmxla mutant dreher displays a moderate reduction of correctly specified mDA neurons. Previously, Lmxlb has been shown to be essential for the specification and maintenance of mDA neurons. However, these mice have lost the isthmic organiser, which is essential for the induction of mDA neurons. Here, we investigated the specific functions of Lmxlb in the ventral neural tube by a Shhcre mediated conditional deletion of Lmxlb. Lmxlb conditional mutants show no defect in mDA neuron specification and maintenance, thus arguing against the central role of Lmxlb in mDA neuron development. Nevertheless, double mutant analyses demonstrate that Lmxla/b regulate the specification and proliferation of mDA progenitors, and their differentiation into mDA neurons in a gene dosage dependent manner. Thus, Lmxla/b play essential roles throughout the development of mDA neurons.

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