The secreted form of Neuregulin-1 in schizophrenia

描述（申请人提供）：精神分裂症是一种毁灭性的神经精神疾病，影响约1.1%的18岁以上的人口。人类和小鼠的遗传研究已经确定了几个精神分裂症易感基因。其中，神经调节蛋白-1（Nrg 1），一种多效性信号分子，被证实为精神分裂症的风险基因（Stefansson et al.，2002;Hall等人，2006;Law等人，2006年）。Nrg 1信号通路的功能变化如何导致精神分裂症是一个重要的研究课题。需要Nrg 1的蛋白水解切割以释放将与ErbB的同源受体相互作用的功能片段 家族发挥细胞-细胞信号传导（福尔斯，2003;Mei和Xiong，2008）。在我们对BACE 1的研究中，最初发现BACE 1是用于切割淀粉样前体蛋白以释放A的β-分泌酶（Vassar等人，1999;Yan等人，1999;Hussain等人，1999;Sinha等人，1999;Lin等人， 2000），我们已经表明BACE 1切割跨膜Nrg 1以释放分泌的含有EGF结构域的N-末端片段并发挥信号传导功能（Hu et al.，2008;Fleck等人，2013年）。具有BACE 1缺陷的小鼠表现出改变的Nrg 1信号传导功能并发展出精神分裂症样表型（Savonenko等人，2008年）。一个有趣的问题是，增强BACE 1基因敲除小鼠的Nrg 1活性是否会改善行为。与此相关，我们最近建立了一种小鼠模型，该模型在四环素（泰特）责任元件（Tet-Off启动子）的控制下表达BACE 1切割的Nrg 1 N-末端片段（称为Nrg 1-ntf）。我们发现Nrg 1-ntf在转基因小鼠（Tg-N1/T小鼠）中的过表达增强了Nrg 1信号传导活性，因为其下游信号分子Akt和Erk被激活。然而，与我们的预期相反，我们的功能研究表明，Tg-N1 /T小鼠发展出精神分裂症样行为，如果关闭转基因表达，这种行为可以逆转。我们实验室和其他实验室的结果表明，异常低或高功能的Nrg 1可能导致精神分裂症。由于精神分裂症易感基因的失调表达可能影响正常的脑发育并导致不同年龄的不同症状的逐渐出现（Piper et al.，2012;Powell，2010;Rapoport等人，2005），我们的目标是测试我们的假设，即在早期发育过程中增加Nrg 1活性，但不是在成年期，有助于成年后的精神分裂症样行为。为了验证我们的假设，在这项研究中，我们提出了两个具体目标。目的1：确定成人Nrg 1活性增加是否对精神分裂症样行为有影响。目的2：探讨N1 /T转基因小鼠精神分裂症样行为的分子机制。

DESCRIPTION (provided by applicant): Schizophrenia is a devastating neuropsychiatric disorder, affecting about 1.1% of the population over the age of 18. Human and mouse genetic studies have identified several schizophrenia susceptibility genes. Among them, neuregulin-1 (Nrg1), a pleiotropic signaling molecule, is confirmed as a risk gene for schizophrenia (Stefansson et al., 2002;Hall et al., 2006;Law et al., 2006). How functional changes in Nrg1 signaling lead to schizophrenia is an important research topic. Proteolytic cleavage of Nrg1 is required to release a functional fragment that will interact with its cognate receptors of the ErbB family to exert cell-cell signaling (Falls, 2003;Mei and Xiong, 2008). In our studies of BACE1, which was initially discovered as the -secretase for cleaving amyloid precursor protein to release A (Vassar et al., 1999;Yan et al., 1999;Hussain et al., 1999;Sinha et al., 1999;Lin et al., 2000), we have shown that BACE1 cleaves transmembrane Nrg1 to release a secreted EGF-domain- containing N-terminal fragment and to exert a signaling function (Hu et al., 2008;Fleck et al., 2013). Mice with deficiency in BACE1 exhibit altered Nrg1 signaling function and develop schizophrenia-like phenotypes (Savonenko et al., 2008). One intriguing question is whether enhancing Nrg1 activity in BACE1-null mice will ameliorate behaviors. Related to this question, we have recently generated a mouse model which expressed BACE1-cleaved Nrg1 N-terminal fragment (termed as Nrg1-ntf ) under the control of tetracycline (Tet) responsible element (Tet-Off promoter). We found that overexpression of Nrg1-ntf in transgenic mice (Tg- N1 /T mice) enhances Nrg1 signaling activity, as its downstream signaling molecules Akt and Erk are activated. However, contrary to our expectations, our functional study shows that Tg-N1 /T mice develop schizophrenia- like behaviors, which can be reversed if transgene expression is switched off. Results from our lab and others imply that abnormally hypo- or hyper-functional Nrg1 can lead to schizophrenia. Since the dys-regulated expression of schizophrenia susceptibility genes may affect normal brain development and lead to the gradual appearance of different symptoms at different ages (Piper et al., 2012;Powell, 2010;Rapoport et al., 2005), we aim to test our hypothesis that increased Nrg1 activity during early development, but not during adulthood, contributes to subsequent schizophrenia-like behaviors in the adult. To test our hypothesis in this study, we propose two specific aims. Aim 1: To determine whether increased Nrg1 activity in the adult has an impact on schizophrenia-like behaviors. Aim 2: To explore molecular mechanisms associated with schizophrenia-like behaviors in N1 /T transgenic mice.