- The developmental road of a dopamine neuron: In search of novel factors in mdDA neuronal development
- Award date
- 16 December 2016
- Number of pages
- Document type
- PhD thesis
- Faculty of Science (FNWI)
- Swammerdam Institute for Life Sciences (SILS)
Mesodiencephalic dopaminergic (mdDA) neurons are involved in motivation, reward, and movement systems in the brain. This group of neurons can be subdivided into different subsets of neurons, which becomes specifically clear during Parkinson’s Disease (PD), when neurons of the substantia nigra degenerate, whereas neurons of the VTA remain relatively intact. Why the degeneration during PD mainly affects neurons of the SNc and how these subsets of neurons are specified remains unclear.
In this thesis we have tried to answer the question how neural progenitor cells in the ventricular zone of the midbrain are specified to become mdDA neurons and how these neurons obtain a subset-specific identity. By means of gene expression analysis we have identified 6 factors that could have a role in the development of these neurons. We have shown that 3 previously unknown factors have a function in early specification of neural progenitor cells and/or late differentiation into the different subsets. Furthermore, we show that one of these factors also has a function in cortical development. Besides these experiments we have developed a technique to electroporate developing mdDA neurons and thereby manipulating gene expression.
The research performed in this thesis provides novel insights in the factors that are important in the development of mdDA neurons and the different subsets. This knowledge can be used in optimizing protocols to culture the correct set of mdDA neurons to use for cell-transplantation therapies in patients with PD.
- Research conducted at: Universiteit van Amsterdam
Thesis (complete) (Embargo until 16 December 2026)
Chapter 1: The life and death of mdDA neurons: an origin story (Embargo until 16 December 2026)
Chapter 2: Expression analyzes of early factors in midbrain differentiation programs (Embargo until 16 December 2026)
Chapter 4: Tcf12 is involved in early cell-fate determination of midbrain dopamine neurons (Embargo until 16 December 2026)
Chapter 5: Tcf4 affects subset specification in mesodiencephalic dopamine neurons (Embargo until 16 December 2026)
Chapter 6: Tcf4 is an essential factor in correct cortical development (Embargo until 16 December 2026)
Chapter 7: Mest/Peg1 is essential for the development and maintenance of a SNc neuronal subset (Embargo until 16 December 2026)
Chapter 8: Focal electroporation of mesodiencephalic dopaminergic neurons (Embargo until 16 December 2026)
Chapter 9: General discussion and summary of main findings (Embargo until 16 December 2026)
Addenda: Nederlandse samenvatting | Dankwoord | List of publications | About the author (Embargo until 16 December 2026)
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