21-P036 Signaling in development – Unravelling engrailed1 function in mesodiencephalic dopaminergic (mdDA) neurons

The mesodiencephalic dopaminergic (mdDA) system is involved in the control of movement and behavior. These neurons are located in three distinct nuclei in the midbrain, one of which is the substantia nigra pars compacta (SN). The loss of dopaminergic neurons in this neuronal population is the neuropathological hallmark of Parkinson’s disease (PD). The homeobox transcription factor engrailed 1 (En1) is expressed in the SN from early in development to adulthood. It has been shown that the En1 participates directly in the regulation of mdDA apoptosis, a proposed mechanism for Parkinson’s disease. Indeed, the deletion of the two En1 leads to the prenatal loss of DA neurons in the SN, via apoptosis. Furthermore, the En1+/;En2 / mice adult phenotype resembles key pathological features of PD – progressive degeneration of dopaminergic neurons restricted to the SN of young adult mice, motor deficits similar to akinesia and bradykinesia, and a lower body weight. The practical goals for this project are to find the downstream targets and interactors of En1, focusing on its role in the survival of the SN mDA neurons. Our general aim is to understand the molecular developmental program of the mdDA system and its maintenance and function, thereby enhancing the success of future clinical intervention in human mdDA pathology.