Genome wide expression profiling of the mesodiencephalic region identifies novel factors involved in early and late dopaminergic development
Koushik Chakrabarty,
Lars Von Oerthel,
Anita Hellemons,
Frédéric Clotman,
Agnès Espana,
Marian Groot Koerkamp,
Frank C. P. Holstege,
R. Jeroen Pasterkamp,
Marten P. Smidt
Affiliations
Koushik Chakrabarty
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
Lars Von Oerthel
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
Anita Hellemons
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
Frédéric Clotman
Université Catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Avenue Hippocrate 55, Box B1.55.11, Brussels, B-1200, Belgium
Agnès Espana
Université Catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Avenue Hippocrate 55, Box B1.55.11, Brussels, B-1200, Belgium
Marian Groot Koerkamp
Microarray Facility, Molecular Cancer Research, UMC Utrecht, 3508 AB Utrecht, The Netherlands
Frank C. P. Holstege
Microarray Facility, Molecular Cancer Research, UMC Utrecht, 3508 AB Utrecht, The Netherlands
R. Jeroen Pasterkamp
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
Marten P. Smidt
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands
Summary Meso-diencephalic dopaminergic (mdDA) neurons are critical for motor control and cognitive functioning and their loss or dysfunction is associated with disorders such as Parkinson's disease (PD), schizophrenia and addiction. However, relatively little is known about the molecular mechanisms underlying mdDA neuron development and maintenance. Here, we determined the spatiotemporal map of genes involved in the development of mdDA neurons to gain further insight into their molecular programming. Genome-wide gene expression profiles of the developing ventral mesencephalon (VM) were compared at different developmental stages leading to the identification of novel regulatory roles of neuronal signaling through nicotinic acthylcholine receptors (Chrna6 and Chrnb3 subunits) and the identification of novel transcription factors (Oc2 and 3) involved in the generation of the mdDA neuronal field. We show here that Pitx3, in cooperation with Nurr1, is the critical component in the activation of the Chrna6 and Chrnb3 subunits in mdDA neurons. Furthermore, we provide evidence of two divergent regulatory pathways resulting in the expression of Chrna6 and Chrnb3 respectively.
