Molecular coding and subset specification of dopamine neurons
generating the meso-limbic and nigro-striatal system
Studying neuronal development in psychiatric disorders
Psychiatric and neurodegenerative diseases like Parkinson's have a great impact on our society. Understanding the biology and function of the neuronal cell groups implicated in these diseases is crucial for designing effective and targeted therapeutic strategies.
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.
The EU-funded mdDANeurodev project aimed to study the molecular and physiological mechanisms implicated in the development and maintenance of these mdDA neurons. Partners were interested in disorders such as schizophrenia, autism and anxiety-related disorders such as depression.
The project combined three distinct levels of research: early patterning, differentiation and axon pathfinding. The ultimate goal was to use the acquired knowledge to design new strategies for disease treatment as well as to provide new leads for drug targeting.
Previous work by the consortium partners had identified a particular molecular pathway to be involved in the formation of mdDA neurons. During the mdDANeurodev study, partners wished to extend their findings and identify the role of specific transcription factors in mdDA subset specification.
Research in the process of early mdDA neuronal phenotype specification revealed the involvement of many pathways and transcription factors. It also demonstrated that the canonical Wnt signalling was not mediated by Lef1, the 'classical' transcription factor of the pathway.
Migration and guidance analysis of mdDA neurons again unveiled an involvement of Wnt signalling pathway components during the early phase of mdDA neuronal development. 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 the diseased state.
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.
Overall, the mdDANeurodev study results provided significant knowledge on the normal development and function of mdDA neurons. This information is vital for understanding situations of perturbed connectivity, such as in cases of neurodegenerative conditions, and aid the design of future cell transplantation approaches.
The project progressed very successfully and was reviewed as excellent: “It has fully achieved its objectives and technical goals and has even exceeded expectations.”
Concept and objectives
Our project is aimed at identifying molecular and physiological mechanisms of the development and maintenance of mesodiencephalic dopaminergic (mdDA) neurons, the neuronal population affected in Parkinson's disease, in affective disorders as schizophrenia and autism, and in anxiety related disorders as depression. The project aims to combine three distinct levels of research, early patterning, differentiation and axon pathfinding. The acquired knowledge will be used to design new strategies to treat the above mentioned patients and provide new leads for drug targeting.
Recent work by the consortium members has led to the proposal of a molecular pathway that leads to the formation of mdDA neurons in a specific region spanning parts of the diencephalon and mesencephalon (reviewed by Smidt and Burbach, 2007). The data has suggested that specific subsets arise in terms of molecular signature and function (reviewed by Smits et al. 2006). Although the overall developmental pathway has been uncovered recently, many questions remain. Therefore, in this proposal we aim to:
Identify the role of transcription factors in mdDA development
Define mdDA subset-specification
Investigate the relation between subset specification and functional units and axon pathfinding codes
In order to achieve this we propose the following key objectives which will be handled through the three Workpackages:
1 Ventricular zone programming and early specification of the mdDA neuronal phenotype
2 Mechanisms of migration and guidance of mdDA neurons
3 Genetic programming, terminal differentiation and maintenance
The project relies on a multidisciplinary genomics and molecular biology approach to unravel the fundamental biological process used to generate and maintain proper functioning mdDA neurons.
The “mdDANEURODEV” project is essential for identifying new fundamental data that may lead to the generation of new therapies for diseases such as Schizophrenia, Autism, depression and addiction. All knowledge obtained in this project will be published, patented and shared by the consortium so the results can be quickly exploited by other research groups and companies that can build upon the data generated within the consortium.
Contribution to the programme “2.1.2 Systems biology”
The project accurately fulfills the objectives of Health-2007-220.127.116.11 call Multidisciplinary fundamental genomics and molecular biology approaches to study basic biological processes relevant to health and disease.
Psychiatric diseases and neurodegenerative diseases as Parkinson's have a great impact on our society. With the increase of the complexity of our society and the increase in mean age, diseases that hamper the cognitive function are having more and more impact.
The current treatment paradigms are collectively based on suppressing symptoms. To make the step towards understanding the disease itself and treating the disease and its onset, new experimental data are crucial. Looking at the last decade enormous progress has been made by the consortium members and others to provide new data on molecular players that are involved in the generation and function of the neuronal cell groups that are directly and indirectly involved in the above-mentioned diseases. Also the possibility to generate new mdDA neurons from human ES-cells to be used in a cell replacement paradigm depends on data describing the basic biological process that generates mdDA neurons.
All consortium members are absolute experts in this field and complement each other in order to expand the area of expertise essential to address the multi-disciplinary approach. This generates confidence that the key objectives described can be fulfilled by this consortium. Moreover, the consortium members are certain that the achievements from this project, as presented here, will fulfill the socio-economic need for basic knowledge of complex diseases to generate basic knowledge essential to perform translational biology in the process of the development of novel medication.