The developmental basis of dopaminergic neuron diversity

描述（由申请人提供）：帕金森病（PD）患者的严重运动缺陷主要是由中脑多巴胺神经元（mDA）的大量丢失引起的。仔细的形态学研究揭示了某些mDA人群的选择性易感性。因此，与位于黑质背侧层或中脑被盖区（A10）的mDA神经元相比，位于黑质腹侧层（SNpc; A9）的mDA神经元更脆弱。这种差异敏感性突出了mDA群体的多样性。我们假设在发育中的中脑中，存在多个不同的mDA祖细胞库，每个mDA祖细胞库产生不同的mDA亚型。我们将试图确定帕金森病中最敏感的多巴胺神经元类型的祖细胞库。因此，我们将谱系追踪一个提出的mDA祖细胞库，并确定其后代是否分布在多巴胺能场的最脆弱区域，即SNpc的腹侧层。接下来我们将为这个DA亚型绘制地形图。总之，这些实验将提供mDA多样性是如何产生的第一个一瞥。阐明这种多样性的发展基础对于理解mDA的差异易感性以及产生准确的ES或iPSC干细胞衍生模型和PD治疗至关重要。 公共卫生相关性：在帕金森氏病中，多巴胺神经元的一个选择子集容易变性。我们的目标是证明这是因为多巴胺神经元与其出生时本质上不同。

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. PUBLIC HEALTH RELEVANCE: In Parkinson's disease, a select subset of dopamine neurons is prone to degeneration. We aim to demonstrate that this is because dopamine neurons are inherently different from the time of their birth.