Molecular specification of dopaminergic neuron diversity

项目总结 多巴胺是由眼睛和大脑中一小部分但有影响力的神经元产生的。因为这件事 神经调节剂在许多精神疾病和疾病中起着关键作用，了解它是如何 建立和维护多巴胺神经元亚群。我们的初步数据显示，丝氨酸-苏氨酸 激酶LKB1是限制视网膜中多巴胺能神经元数量所必需的。此外，我们确定 新的多巴胺能细胞亚群，并表明LKB1是细胞固有的抑制中间神经元所需的 使用分子和神经遗传学方法调节多巴胺神经元多样性。这是一个令人信服的结果 因为控制产生多巴胺的神经元的数量和类型的因素仍然难以捉摸。 为了了解LKB1如何调节多巴胺神经元多样性，我们设计了一种策略，包括 神经识别和连接图谱，细胞类型特定的交叉遗传和病毒策略，分子 以及生化研究和功能分析。我们提出了三个目标。在目标1中，我们问LKB1是否 在空间和时间上足以指示多巴胺神经元的多样性，通过在特定的 在特定的时间和地点。在目标2中，我们确定了LKB1的功能机制并进行了测试 认为LKB1-AMPK信号起关键作用的假说。在目标3中，我们将分析扩展到中脑 为了测试LKB1是否同样需要在与疾病相关的大脑区域限制多巴胺神经元 多样性。找出精确控制多巴胺神经元多样性的激酶途径是令人惊讶的，所以 完成这些目标将显著提高我们对多巴胺能神经元是如何被赋予的理解 以其独特的特性。此外，这些结果将为恢复 在疾病的背景下产生多巴胺。

PROJECT SUMMARY Dopamine is produced by a small but impactful subset of neurons in the eye and brain. Because this neuromodulator plays a critical role in a host of mental illnesses and diseases, it is vital to understand how dopamine neuron subsets are established and maintained. Our preliminary data show that the serine-threonine kinase LKB1 is required to restrict the number of dopaminergic neurons in the retina. In addition, we identify new dopaminergic cell subsets and show that LKB1 is cell-intrinsically required in inhibitory interneurons to modulate dopamine neuron diversity using molecular and neurogenetic approaches. This is a compelling result because factors that control the number and type of neurons that produce dopamine have remained elusive. To understand how LKB1 regulates dopamine neuron diversity, we have devised a strategy encompassing neural identity and connectivity mapping, cell-type specific intersectional genetic and viral strategies, molecular and biochemical studies, and functional analysis. We propose three aims. In Aim 1, we ask whether LKB1 is spatially and temporally sufficient to instruct dopamine neuron diversity by modulating this kinase in specific locations and at particular times. In Aim 2, we identify the mechanism through which LKB1 functions and test the hypothesis that LKB1-AMPK signaling plays a critical role. In Aim 3, we extend our analysis to the midbrain to test whether LKB1 is similarly required in this disease-relevant brain region to limit dopamine neuron diversity. Identifying a kinase pathway that precisely controls dopamine neuron diversity is surprising, so completing these aims will markedly advance our understanding of how dopaminergic neurons are endowed with their unique properties. In addition, these results will provide new therapeutic avenues for restoring dopamine production in the context of disease.