Ventral Mesencephalon-Enriched Genes that Regulate the Development of Dopaminergic Neurons in Vivo

Jiawei Zhou

Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031

Mesodiencephalic dopaminergic (mDA) neurons are essential for the control of multiple brain functions including movement control, emotion, and reward. Dysfunction of the mDA system is involved in the pathogenesis of several mental and neurological diseases such as Parkinson’s disease (PD) and schizophrenia, of which some are considered to have a neurodevelopmental origin. Currently no effective treatment is available for PD that alters progression of the disease itself. Because of poor understanding of the molecular mechanisms controlling mDA neuron development, attempts at restorative treatment of PD using neural transplantation and drug therapy have been hampered in the last two decades. The application of stem cell-derived mDA neurons in PD treatment likely faces similar problems. Thus studies on mDA neuron development including their specification, differentiation, migration and survival, will promote our understanding of mechanisms of brain development and have an impact on developing novel approaches for the treatment of neurodegenerative diseases such as PD.

We aimed to establish the expression profiles of genes involved in this process and unravel genetic programs that control late development of mDA neurons. We compared genome-wide gene expression profiles of developing mouse ventral mesencephalon (VM) using microarrays. We identified a set of genes that show spatially and temporally restricted expression in the VM in an Ngn2-dependent manner and are potentially important for mDA neuron development. Functional analysis on mice lacking the VM-specific gene Ebf1 revealed that Ebf1 is essential for the terminal migration of mDA neurons in the substantia nigra pars compacta. Taken together, we identified a set of VM-enriched genes that are important for mDA neuron development. Our analysis also provides a genetic framework for further investigation of the molecular mechanisms mediating mDA neuron development.