Genetics of Neuronal Signaling Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Graduate Program in Neuroscience, State University of New York at Stony Brook, Stony Brook, New York 11794.
J Neurosci. 2024 Oct 23;44(43):e0063242024. doi: 10.1523/JNEUROSCI.0063-24.2024.
Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by γ-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (VL) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The VL mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. VL mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the VL DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of VL mouse and humans with SCZ.
神经调节蛋白 1（Nrg1）信号对于神经元的发育和功能至关重要，从命运决定到突触可塑性。III 型 Nrg1 是一种突触蛋白，与受体 ErbB4 进行双向信号传递。正向信号参与 ErbB4 的磷酸化，而反向信号参与两种已知的机制：（1）局部轴突 PI3K-AKT 信号和（2）通过 γ-分泌酶切割导致细胞内结构域（ICD）的胞质释放，其可以转运到细胞核（Bao 等人，2003 年；Hancock 等人，2008 年）。为了剖析这些替代信号策略对神经元发育的贡献，我们生成了一种转基因小鼠，该小鼠在 Nrg1 跨膜结构域中具有一个错义突变（VL），该突变破坏了核反向信号传递，对正向信号传递或局部反向信号传递的影响最小，并且先前与精神病有关（Walss-Bass 等人，2006 年）。我们结合 RNA 测序、神经干细胞的逆转录病毒命运图谱分析、行为分析以及转录组数据的各种网络分析，研究了在雄性和雌性小鼠的齿状回（DG）中断 Nrg1 核反向信号传递的影响。VL 突变会损害 Nrg1 ICD 的核易位，并改变 DG 中的基因表达。VL 小鼠表现出干细胞增殖减少、细胞周期动力学改变、命运决定缺陷和树突发育不良。已知精神分裂症（SCZ）易感性基因的同源物在 VL DG 中失调。这些基因与其他失调基因协调了更大的网络。加权基因相关性网络分析和蛋白质相互作用网络分析显示，VL 小鼠和患有 SCZ 的人类 DG 转录组之间存在惊人的相似性。
