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

建立多巴胺能系统中的神经元多样性：转录因子 Bcl11a 的作用

• 批准号: 283882858
• 负责人: Professorin Dr. Sandra Blaess
• 金额: --
• 依托单位: Institut für Rekonstruktive Neurobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/283882858?language=en
• 关键词: Establishing; neuronal; diversity; dopaminergic; system

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.

中脑多巴胺能神经元（MbDN）调节运动、奖励行为和认知过程。MbDN的退化或功能障碍与几种常见的人类疾病有关，包括帕金森病、抑郁症和精神分裂症。作为大脑中一个相对较小的神经元群，mbdn是如何促成如此多样化的功能的，目前还没有完全了解。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，在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MbDN亚群发育过程中建立的转录因子代码通过决定这些特定MbDN亚群的分子组成、连通性和功能特性来定义它们的身份。通过比较胚胎发育期间两个不同的MbDN亚群的基因表达谱，我们已经确定了一些转录因子，这些转录因子在发育和成年大脑的MbDN亚群中表达。我们建议研究其中一个已确定的因子，kr<s:1> ppel样锌指转录因子Bcl11a，如何决定MbDN亚群的功能身份。我们将结合遗传谱系分析、光遗传学方法和病毒追踪方法来表征表达bcl11a的MbDN亚型的投射、生理和功能。此外，我们将生成条件敲除小鼠模型，使MbDN中的Bcl11a特异性失活，并分析失活对MbDN命运和生存的影响以及对条件敲除小鼠行为的影响。我们的分析将深入了解MbDN亚类的发育决定分子细胞身份如何决定它们在成人大脑中的连通性和功能。

项目成果

BMP/SMAD Pathway Promotes Neurogenesis of Midbrain Dopaminergic Neurons In Vivo and in Human Induced Pluripotent and Neural Stem Cells

• DOI: 10.1523/jneurosci.1540-17.2018
• 发表时间: 2018-02-14
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Jovanovic, Vukasin M.;Salti, Ahmad;Brodski, Claude
• 通讯作者: Brodski, Claude

The zinc-finger transcription factor GLI3 is a regulator of precerebellar neuronal migration

锌指转录因子 GLI3 是小脑前神经元迁移的调节因子

• DOI: 10.1242/dev.166033
• 发表时间: 2018
• 期刊: Development
• 影响因子: 4.6
• 作者: E Martinez-Chavez;C Scheerer;A Wizenmann;S Blaess
• 通讯作者: S Blaess

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

• DOI: 10.1111/ejn.14345
• 发表时间: 2019-02
• 期刊: The European Journal of Neuroscience
• 作者: Beatrice Weykopf;S. Haupt;Johannes Jungverdorben;L. Flitsch;Matthias Hebisch;Guang-Hui Liu;Keiichiro Suzuki;J. Belmonte;M. Peitz;S. Blaess;A. Till;O. Brüstle

Correct setup of the substantia nigra requires Reelin-mediated fast, laterally-directed migration of dopaminergic neurons

• DOI: 10.7554/elife.41623
• 发表时间: 2019-01
• 期刊: eLife
• 影响因子: 7.7
• 作者: A. R. Vaswani;Beatrice Weykopf;C. Hagemann;Hans-Ulrich Fried;O. Brüstle;S. Blaess