MDDANEURODEV

Molecular coding and subset specification of dopamine neurons generating the the meso-limbic and nigro-striatal system

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'This project aims to elucidate the molecular coding of meso-diencephalic dopaminergic (mdDA) neurons forming the complex meso-limbic and nigro-striatal dopaminergic system in the vertebrate central nervous system. Recent advances in molecular and developmental biology have shown that this system harbors u multitude of functional units that are defined by spatial and temporal cues and are represented by specific molecular codes. These codes are essential to understand specific mdDA neuronal pathology as Parkinson's diseases and schizophrenia. In this collaborative project we gather the expertise on early and late development, cross species molecular-coding conservation, migration and axonal pathfinding to capture the significance of the understanding of mdDA neuronal development to generate a real advance in clinical understanding and treatment of mdDA pathology.'

Introduzione (Teaser)

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.

Descrizione progetto (Article)

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 Mddaneeurodev project aimed to study the molecular and physiological mechanisms implicated in the development and maintenance of these mdDA neurons. Partners were particularly 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 Mddaneeurodev 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.