The developmental basis of dopaminergic neuron diversity

描述（由申请人提供）：帕金森病（PD）患者的剧烈运动障碍主要是由中脑多巴胺神经元（mDA）的大量丧失引起的。仔细的形态计量学研究揭示了某些mDA群体的选择性易感性。因此，与位于黑质致密部背层或腹侧被盖区（A10）的mDA神经元相比，位于黑质致密部腹侧层（SNpc; A9）的mDA神经元更脆弱。这种不同的易感性突出了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祖细胞池，每个祖细胞池都产生不同的mDA亚型。我们将尝试确定PD中最易感的多巴胺神经元类型的祖细胞池。因此，我们将对一个提议的mDA祖细胞池进行谱系追踪，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子类型开发地形图。总之，这些实验将提供对mDA多样性是如何产生的初步了解。阐明这种多样性的发育基础对于理解mDA的不同易感性，以及生成准确的ES或iPSC干细胞衍生模型和PD治疗方法至关重要。

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.