Engineering Midbrain Dopamine Neurons by Forced Expression of a Novel Dopamine Cell Determinant in Pre-Clinical Model Embryonic Stem Cells

Understanding how the different cells of the brain are generated during embryonic development is one of the fundamental questions in biology. Recent studies have elucidated several key mechanisms explaining how different neuronal cell types are generated. However, surprisingly little is known about the process that underlies the generation of the dopamine cells that degenerate in Parkinson's disease. Elucidating the molecular program that control the generation of dopamine cells should facilitate strategies to generate dopamine neurons from stem cells and may also have relevance for understanding the pathology of dopamine neurons in Parkinson's patients. In preliminary experiments, we have identified several novel factors implicated in dopamine cell generation. In this project, we aim to characterize the functional role of these factors in developing dopamine cells, and further examine the possible use of these factors to effectively produce dopamine neurons from stem cells. UPDATE JUNE 2006: The researchers discovered two proteins, Lmx1a and Msx1. Both are transcription factors, a class of proteins whose job is to turn other genes in the cell on and off. The researchers further discovered that Lmx1a and Msx1 are required for certain molecular events to occur. These events play an important role in dopamine neuron differentiation. The researchers also showed that expression of Lmx1a results in much more robust generation of dopamine neurons than had been seen before. To follow up on the promising findings, the Foundation quickly approved supplemental funding for the researchers. These funds will support new experiments to establish whether the stem cell-derived dopamine neurons generated using Lmx1a and Msx1 yield improved transplantation results in rodent models of Parkinson's.