Abstract
The last few years, considerable research has been realized to discover the molecular make-up of mdDA neurons, in order to generate specific mdDA populations that can be used for stem cell based replacement-therapy in Parkinson's disease (PD). The challenge is to identify genetic programs that are responsible for the generation
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of different mdDA neuronal subsets, and their distinct migrational and axonal projection patterns. Early transcription factors Lmx1a and Lmx1b have been suggested to be essential in either the onset and maintenance of the mdDA system, or the neurogenesis of mdDA progenitors. In addition, Lmx1a is an efficient inducer of mdDA neurons from embryonic stem cells. Despite these data, not much is known about the exact function of both factors during early and late development, or in mature mdDA neurons. To gain a better understanding of the detailed functions of Lmx1a and Lmx1b, we characterized their downstream genetic programs. By means of expression micro-array analysis of gain-and-loss-of-function of Lmx1a and Lmx1b in cell lines, and in embryonic mouse mutants, we identified a large set of downstream target genes of both transcription factors, many of them suggested to function in mdDA neurons. Regulation of Lmx1a on several known mdDA genes, and novel Lmx1a targets, was found, and importantly, this regulation was subset specific in a rostral-lateral group of developing and mature mdDA neurons, highlighting the complex in vivo phenotype whereby loss of Lmx1a results in a loss of an SNc subset of mdDA neurons mainly. Lmx1b appeared to be involved in many processes such as neuronal migration, axonal guidance and in Wnt-signaling. Next to this, we found a novel role for transcription factor Phox2b, that might be required for the development of a caudal subset of mdDA neurons. Finally, both Lmx1a and Lmx1b seem to function in cooperation with Nurr1; Lmx1a via regulating this gene in a genetic cascade, and Lmx1b via a proposed protein binding to the previously identified Nurr1 transcriptional protein complex. In conclusion, the identification of novel Lmx1a and Lmx1b molecular programs have provided an essential insight in the roles that these transcription factors play during mdDA neuronal development. The existence of different developmentally regulated mdDA subsets was demonstrated, contributing to a better understanding of the generation of functionally distinct mdDA neurons, which eventually might provide insight in subset specific vulnerability as exemplified in PD
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