Neuronal development in psychiatric disorders
Meso-diencephalic dopaminergic (mdDA) neurons are involved in the control of voluntary movements and the regulation of emotion-related behaviour. They are affected in many neurological and psychiatric disorders, including Parkinson's disease and schizophrenia. Partners with the MDDANEURODEV (Molecular coding and subset specification of dopamine neurons generating the meso-limbic and nigro-striatal system) initiative were particularly interested in disorders such as schizophrenia, autism and some anxiety-related disorders. The knowledge was used to design new strategies for disease treatment as well as provide new leads for drug targeting. Previous work by the consortium partners had identified a particular molecular pathway involved in the formation of mdDA neurons. The project combined three distinct levels of research: early patterning, differentiation and axon pathfinding. Research in the process of early mdDA neuronal phenotype specification demonstrated that canonical Wnt signalling was not mediated by Lef1, the 'classical' transcription factor of the pathway. However, Lmx1a is an important target in mdDA neurons of B-catenin signalling. Moreover, the team completed analysis at the systems biology level of several signalling pathway components’ expression in the proximity of dopamine neurons in zebrafish. Migration and guidance analysis of mdDA neurons again unveiled an involvement of Wnt signalling pathway components during the early phase of mdDA neuronal development. Results indicated that mdDA neurons change their mode of migration from radial to tangential as they adopt their final position. This involves pathways that are regulated by chemokines Cxcl12/Cxcr4. At a later stage of genetic programming, terminal differentiation and maintenance, scientists concentrated on the downstream targets of the critically important homeodomain Pitx3 transcription factor. The involvement of retinoic acid signalling in the process might provide a tool to interfere with the mdDA transcriptional profile in diseases like Parkinson’s. Another interesting finding was that Otx2 was required for the neurogenesis of mdDA neurons. This molecule may confer resistance to the neurotoxin MPTT, which mimics Parkinsonian neurodegeneration. MDDANEURODEV study results have provided significant knowledge on the normal development and function of mdDA neurons. Vital for understanding situations of perturbed connectivity in cases of neurodegenerative conditions, this could aid the design of future cell transplantation approaches.
Keywords
Parkinson’s, dopamine neuron, mdDA, MDDANEURODEV, signalling
