FOXA2 and the birth and death of midbrain dopamine neurons

The potential use of functional dopamine neurons derived from stem cells in the study and treatment of Parkinson’s disease has focused attention on the developmental origin of these cells. To optimize methods for the in vitro differentiation of dopamine neurons, a more precise understanding of their embryonic development is necessary. Previous studies suggested that dopamine neuron fate is induced by the floor plate and the morphogen. Shh. I have found that, in fact, dopamine neurons are derived from the Shh-expressing cells of the midbrain floor plate, itself. The forkhead transcription factor, Foxa2, is expressed in the floor plate and critical for the development of dopamine neurons. I observed that Foxa2 continues to be expressed in dopamine neurons in the adult substantia nigra and ventral tegmental area, where it regulates the survival of dopamine neurons. Mice carrying only one copy of the foxa2 gene showed a spectrum of motor deficits reminiscent of Parkinson’s disease, including bradykinesia, tremors, and rigidity. Also similar to Parkinson’s disease, these movement abnormalities were accompanied by a progressive loss of midbrain dopamine neurons. The foxa2 heterozygous mouse is the first mouse model of age-dependent dopamine neuron degeneration. This new genetic model offers an opportunity to study the mechanism underlying dopamine neuron degeneration as well as the associated behavioural changes. This work suggests that forkhead proteins play a central role in the biology of Parkinson’s disease and that targeting the foxa2 gene may be a new approach in stem cell-based and pharmacological therapies for Parkinson’s disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo