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EZH2 Influences mdDA Neuronal Differentiation, Maintenance and Survival
Iris Wever1, Lars von Oerthel1, Cindy M R J Wagemans1
1Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands.
Frontiers in Molecular Neuroscience
|February 2, 2019
Summary
Histone methyltransferase EZH2 is crucial for developing mesodiencephalic dopaminergic (mdDA) neurons and maintaining their identity and survival in adult stages, impacting Parkinson's disease models.
Area of Science:
- Neuroscience
- Developmental Biology
- Epigenetics
Background:
- Mesodiencephalic dopaminergic (mdDA) neurons exhibit molecular heterogeneity, influencing selective degeneration in Parkinson's disease.
- Transcriptional programs and potentially histone modifications regulate mdDA neuron subset development and maintenance.
Purpose of the Study:
- To investigate the role of histone methyltransferase EZH2 in the development and maintenance of mdDA neurons.
- To determine EZH2's impact on mdDA neuron subset identity and survival.
Main Methods:
- Generated conditional knock-out (cKO) mice using En1Cre and Pitx3Cre drivers to delete Ezh2 at different developmental stages.
- Analyzed TH+ neuron numbers, subset markers (Ahd2, Cck), and behavioral changes in Ezh2 cKO mice.
Main Results:
- Early Ezh2 deletion impaired TH+ neuron generation, particularly affecting rostrolateral populations.
- Post-mitotic Ezh2 deletion led to ectopic Cck expression, reduced Ahd2 expression, progressive VTA TH+ cell loss, and impaired climbing behavior in adult mice.
Conclusions:
- EZH2 is essential for the proper generation of mdDA neurons during development.
- EZH2 plays a critical role in preserving neuronal subset identity and survival of mdDA neurons in adult stages.
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