Department of Cell and Molecular Biology, Tulane University, 6400 Freret Street, New Orleans, LA 70118, USA.
Neurosci Res. 2011 Jun;70(2):155-63. doi: 10.1016/j.neures.2011.02.009. Epub 2011 Feb 23.
The NRG1 growth factor and ERBB4 receptor have been identified as leading schizophrenia risk genes. Although NRG1 and ERBB4 have been shown to modulate neuronal functions involved in schizophrenia, including both GABAergic and glutamatergic synapses, the exact molecular mechanisms remain poorly understood. Here we investigated ERBB4 intracellular domain, 4ICD, transactivator function in rat hippocampal cultures by inhibiting γ-secretase mediated ERBB4 regulated intramembrane proteolysis (RIP). NRG1 stimulation resulted in a dramatic increase in the number of hippocampal cells displaying nuclear 4ICD which was abolished in cultures pretreated with the γ-secretase inhibitor compound E (CE). To identify NRG1-4ICD transactivated genes we compared global gene expression profiles of hippocampal cultures stimulated with NRG1 in the absence or presence of CE. In concordance with the contribution of NRG1-ERBB4 signaling to dendritic spine maturation and schizophrenia, global gene expression analysis followed by Ingenuity Pathway Analysis of the dataset identified NRG1-4ICD regulated genes significantly represented in semaphorin signaling and actin cytoskeletal plasticity and multiple genes with confirmed roles in dendritic spine morphogenesis. Using the power of global gene expression analysis our data provides a proof-of-concept supporting a role for non-canonical NRG1-4ICD signaling in the regulation of gene expression contributing to normal and schizophrenic neuronal function.
NRG1 生长因子和 ERBB4 受体已被确定为导致精神分裂症的主要风险基因。虽然 NRG1 和 ERBB4 已被证明可以调节与精神分裂症相关的神经元功能，包括 GABA 能和谷氨酸能突触，但确切的分子机制仍知之甚少。在这里，我们通过抑制 γ-分泌酶介导的 ERBB4 调节的跨膜蛋白水解（RIP），研究了大鼠海马培养物中 ERBB4 细胞内结构域 4ICD 的转激活功能。NRG1 刺激导致海马细胞中显示核 4ICD 的数量急剧增加，而在用 γ-分泌酶抑制剂化合物 E（CE）预处理的培养物中则消除了这种增加。为了鉴定 NRG1-4ICD 转激活基因，我们比较了在不存在或存在 CE 的情况下，NRG1 刺激的海马培养物的全基因组表达谱。与 NRG1-ERBB4 信号对树突棘成熟和精神分裂症的贡献一致，对数据集进行的全基因组表达分析和 Ingenuity 通路分析表明，NRG1-4ICD 调节的基因在信号转导和肌动蛋白细胞骨架可塑性中显著代表，并且多个基因在树突棘形态发生中具有确认的作用。利用全基因组表达分析的强大功能，我们的数据提供了一个概念验证，支持非经典 NRG1-4ICD 信号在调节与正常和精神分裂症神经元功能相关的基因表达中的作用。
