Parkinson’s disease (PD), a severely debilitating adult-onset neurodegenerative condition, is characterized by a substantial depletion of a subset of midbrain dopamine neurons (mDA). This loss of mDA accounts for most motor deficits observed in this disease. Recent studies have revealed that specific subsets of mDA are lost in PD. This selective mDA neuron susceptibility in PD highlights heterogeneity of the mDA system. Thus, replacing specific subtypes of mDA, as opposed to generic mDA, has been highlighted as an important goal of stem cell based therapies for PD 15.
Our goal is to understand how different mDA subtypes are generated. Here, we propose experiments to define how in the embryo, midbrain progenitor cells are directed by specific gene/gene combinations to yield distinct mDA subtypes. To do so, we will indelibly label specific progenitor cell populations using conditional genetic techniques we and others have developed, and determine what subtypes of mDA are produced from distinct progenitor pools. These experiments will define the developmental basis for mDA diversity. Understanding the developmental cascades underlying mDA diversity will be critical for generating stem cell derived therapies or models of PD.