Establishing neuronal diversity in the dopaminergic system: the role of the transcription factor Bcl11a

中脑多巴胺能神经元（MbDN）调节运动，奖励行为和认知过程。MbDN的变性或功能障碍涉及几种常见的人类疾病，包括帕金森病、抑郁症和精神分裂症。MbDNs在大脑中构成相对较小的神经元群体，如何能够有助于实现如此多样化的功能仍然没有完全了解。最近的证据表明，MbDN亚型可以根据其在出生后大脑中的分子或神经化学特征来定义。此外，研究表明，解剖学和生理学上离散的MbDN介导行为的不同方面。目前尚不清楚MbDN的这种多样性是如何在发育过程中建立的，以及特定的分子身份如何与MbDN亚型的功能身份相关联。我们假设，在开发过程中建立在MbDN亚群中的转录因子编码通过确定其分子组成、连接性和功能特性来定义这些特定MbDN亚群的身份。通过比较两个不同的MbDN亚组在胚胎发育过程中的基因表达谱，我们已经确定了一些转录因子，这些转录因子在发育和成人大脑中的MbDN亚组中表达。我们建议研究如何确定的因素之一，Krüppel样锌指转录因子Bcl11a，确定MbDN亚群的功能特性。我们将通过结合遗传谱系分析、光遗传学方法和病毒追踪方法来表征表达Bcl 11 a的MbDN亚型的预测、生理和功能。此外，我们将产生一个条件性基因敲除小鼠模型，在MbDN中特异性地抑制Bcl11a，并分析失活对MbDN命运和存活以及对条件性基因敲除小鼠行为的影响。我们的分析将提供深入了解MbDN亚类的发育决定的分子细胞身份如何决定它们在成人大脑中的连接和功能。

Midbrain dopaminergic neurons (MbDN) modulate movement, reward behavior and cognitive processes. Degeneration or dysfunction of MbDN is implicated in several common human disorders including Parkinson disease, depression and schizophrenia. How MbDNs, which constitute a relatively small neuronal population in the brain, can contribute to such diverse functions is still not fully understood. Recent evidence indicates that MbDN subtypes can be defined based on their molecular or neurochemical profile in the postnatal brain. In addition, it has been shown that anatomically and physiologically discrete MbDNs mediate distinct aspects of behavior. It remains unclear how this diversity of MbDNs is established during development and how a particular molecular identity is linked to the functional identity of an MbDN subtype. We hypothesize that transcription factor codes that are established in MbDN subsets during development define the identity of these specific MbDN subsets by determining their molecular make-up, their connectivity and their functional properties. By comparing gene expression profiles of two distinct MbDN subgroups during embryonic development, we have identified a number of transcription factors, which are expressed in subsets of MbDNs in the developing and adult brain. We propose to study how one of the identified factors, the Krüppel-like zinc finger transcription factor Bcl11a, determines the functional identity of an MbDN subpopulation. We will characterize the projections, physiology and function of the Bcl11a-expressing MbDN subtypes by combining genetic lineage analysis, optogenetic approaches and viral tracing methods. Moreover, we will generate a conditional knock-out mouse model to inactivate Bcl11a specifically in MbDN and analyze the consequences of the inactivation on MbDN fate and survival and on the behavior of the conditional knock-out mice. Our analysis will provide insight into how the developmentally determined molecular cell identity of MbDN subclasses determines their connectivity and function in the adult brain.