The developmental basis of dopaminergic neuron diversity

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DESCRIPTION (provided by applicant): The drastic motor deficit in Parkinson's disease (PD) patients is largely caused by a substantial loss of midbrain dopamine neurons (mDA). Careful morphometric studies have revealed a selective susceptibility of certain mDA populations. Thus, mDA neurons found in the ventral tier of the substantia nigra pars compacta (SNpc; A9) are more vulnerable, compared to mDA located in the dorsal tier of the SNpc, or in the Ventral Tegmental Area (A10). This differential susceptibility highlights the diversity of mDA populations. We hypothesize that in the developing midbrain, there are multiple distinct mDA progenitor pools, each of which gives rise to distinct mDA subtypes. We will attempt to determine the progenitor pool for the most susceptible type of dopamine neuron in PD. Accordingly, we will lineage trace one proposed mDA progenitor pool and determine whether its descendents populate the most vulnerable regions of the dopaminergic field i.e. the ventral tier of the SNpc. Next we will develop topographic maps for this DA subtype. Together, these experiments will provide a first glimpse into how mDA diversity is generated. Elucidating the developmental basis for this diversity will be critical for understanding differential susceptibility of mDA, as well as generating accurate ES or iPSC stem cell derived models and therapies for PD.