Identification and characterization of genes expressed by the midbrain dopaminergic neurons

The midbrain dopaminergic (mDA) neurons are the main source of dopamine in the brain. The goal of this study was to identify and characterize genes effective during the intermediate period between induction and full differentiation of the mDA neurons. The generation of En chimeric animals permitted to show that the mDA neurons require the Engrailed (En) genes cell autonomously for their survival, and the over-expression experiment of En-1 suggested that the En genes are not required for the formation of mDA precursor cells. I identified more genes specifically expressed by the mDA neurons using a PCR-based differential display screen. Three genes have been further characterized in this study: The hepatocyte nuclear factor 3 a (HNF3a), the neuronal and B-cell differentiation factor, Olf-1/Ebf, and the neuregulin receptor, ErbB4. HNF3a is expressed in the precursors of the mDA neurons at E9 and continues to be expressed in the postmitotic cells until adulthood. Analyses of the mDA neurons from mice lacking HNF3a showed that HNF3a is not required for the early development of mDA neurons, but a role in their maintenance is still possible. ErbB4 is expressed in the mDA neurons from E11.5 until adulthood, specifying the rostral part of the substantia nigra compacta. Analyses the mDA neurons of adult mice lacking ErbB4, suggested that the expression of ErbB4 after E11 is not essential for the mDA survival, although its involvement into their early fate determination and neural differentiation is a possibility. The Olf-1/Ebf gene is expressed transiently in mouse mDA neurons from E10 to E13. Ectopic expression of Olf-1/Ebf leads to ectopic mDA neurons, suggesting that Olf-1/Ebf may be involved in mDA neurons specification and differentiation. Finally, it was shown that neither HNF3a nor Olf-1/Ebf is regulated by Nurr1 or the En genes. Thereby suggesting that multiple parallel pathways control the development of the mDA neurons.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Universität Heidelberg

Year

2002

Author dc:creator

• Thuret, Sandrine

Contributors dc:contributor

• Dr. Michael Brand

Repository record source_url

http://www.ub.uni-heidelberg.de/archiv/2019

OAI identifier oai:identifier

oai:archiv.ub.uni-heidelberg.de:2019