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The functional relevance of neuregulin1-III-mediated bidirectional signaling in prefrontal cortex of mouse

小鼠前额皮质中纽兰格林1-III介导的双向信号传导的功能相关性

基本信息

批准号：
394716173
负责人：
Professor Dr. Weiqi Zhang
金额：
--
依托单位：
Klinik für Psychische Gesundheit
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/394716173?language=en
关键词：
functional relevance neuregulin1 III mediated

项目摘要

Schizophrenia is a serious mental disorder that can have devastating consequences for patients. Genes encoding neuregulin-1 (NRG1) and its signaling partner receptor tyrosine-protein kinase ErbB-4 (ERBB4) belong to the core candidate genes for the disease. In the adult human brain, different NRG1 protein isoforms are expressed, of which the insoluble NRG1-type III is the most abundant isoform. Until now, the function of all NRG1 isoforms is supposed to be mainly mediated by the interaction of the EGF-like domain of NRG1 with the ERBB4 protein. It is therefore very surprising that, for instance, inhibitory synaptic transmission was elevated in Nrg1-mouse mutants, while it was impaired in Erbb4 mutants. These and other at first sight contradictory data support the notion that the function of NRG1 might be only partly mediated by activation of an ERBB4-dependent pathway. At least one additional ERBB4-independent pathway should also exist, as suggested by in-vitro data. Thus, uncovering the diversity of NRG1-mediated signaling in brain arises as a crucial step in our understanding of the pathophysiology of schizophrenia. Based on published data and our own findings, we therefore hypothesize that NRG1-III activates bidirectionally an ERBB4-dependent (forward) and -independent (backward) signaling pathways AND, that both of them are pivotal for the normal function of the brain. In the current project, specifically designed Nrg1-III transgenic mouse lines will allow us to directly investigate the brain functions of NRG1-III- mediated "forward & backward signaling" in defined synapses of prefrontal cortex and hippocampus that are important for the central control of emotion as well as in the pathogenesis of Schizophrenia.

精神分裂症是一种严重的精神疾病，可能给患者带来毁灭性的后果。编码神经调节蛋白-1（NRG1）及其信号伙伴受体酪氨酸蛋白激酶ErbB-4（ERBB4）的基因属于该疾病的核心候选基因。在成人大脑中，表达不同的NRG1蛋白亚型，其中不溶性NRG1-III型是最丰富的亚型。到目前为止，所有 NRG1 亚型的功能被认为主要是通过 NRG1 的 EGF 样结构域与 ERBB4 蛋白的相互作用介导的。因此，非常令人惊讶的是，例如，抑制性突触传递在 Nrg1 小鼠突变体中升高，而在 Erbb4 突变体中却受损。这些和其他乍一看相互矛盾的数据支持这样的观点：NRG1 的功能可能仅部分由 ERBB4 依赖性途径的激活介导。正如体外数据所表明的，至少还应该存在一种额外的 ERBB4 独立途径。因此，揭示大脑中 NRG1 介导的信号的多样性是我们理解精神分裂症病理生理学的关键一步。因此，根据已发表的数据和我们自己的研究结果，我们假设 NRG1-III 双向激活 ERBB4 依赖性（前向）和独立（后向）信号通路，并且这两种信号通路对于大脑的正常功能都至关重要。在当前的项目中，专门设计的Nrg1-III转基因小鼠系将使我们能够直接研究前额叶皮层和海马体突触中NRG1-III介导的“前向和后向信号传导”的大脑功能，这对于情绪的中枢控制以及精神分裂症的发病机制非常重要。