The secreted form of Neuregulin-1 in schizophrenia

描述(申请人提供)：精神分裂症是一种破坏性的神经精神疾病，影响约1.1%的18岁以上人口。人类和小鼠的遗传学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(Nrg1)，一种多效性信号分子，被确认为精神分裂症的危险基因(Stefansson等人，2002年；Hall等人，2006年；Law等人，2006年)。Nrg1信号的功能变化如何导致精神分裂症是一个重要的研究课题。Nrg1需要蛋白水解性切割才能释放与其同源受体ErbB相互作用的功能片段 家庭发挥细胞-细胞信号(Falls，2003；Mei和熊，2008)。在我们对BACE1的研究中，BACE1最初被发现是裂解淀粉样前体蛋白以释放A的分泌酶(Vassar等人，1999；Yan等人，1999；Hussain等人，1999；Sinha等人，1999；Lin等人， 2000年)，我们已经证明BACE1裂解跨膜Nrg1释放一个分泌的含有EGF结构域的N-末端片段并发挥信号功能(Hu等人，2008；Fleck等人，2013)。BACE1缺乏的小鼠表现出Nrg1信号功能的改变，并发展为精神分裂症样表型(Savonenko等人，2008年)。一个耐人寻味的问题是，增强BACE1基因缺失小鼠的Nrg1活性是否会改善行为。针对这个问题，我们最近建立了一个在四环素(Tet)负责元件(Tet-off启动子)控制下表达BACE1裂解的Nrg1 N末端片段(称为Nrg1-NTF)的小鼠模型。我们发现，在转基因小鼠(TG-N1/T小鼠)中过表达Nrg1-NTF增强了Nrg1信号活性，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小鼠出现了类似精神分裂症的行为，如果转基因表达被关闭，这种行为可以逆转。我们的实验室和其他实验室的结果表明，Nrg1功能异常低下或过度可能导致精神分裂症。由于精神分裂症易感基因的异常调节表达可能会影响正常的大脑发育，并导致不同年龄段不同症状的逐渐出现(Piper等人，2012；Powell，2010；Rapoport等人，2005)，我们的目标是检验我们的假设，即Nrg1在早期发育期间增加的活动，而不是在成年期，有助于随后的成人精神分裂症样行为。为了验证我们在这项研究中的假设，我们提出了两个具体的目标。目的1：确定成人Nrg1活性增加是否对精神分裂症样行为有影响。目的：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.