2019 Vol. 10, No. 4

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. In this issue, Ling et al. generate a non-integrative iPSC-based disease model for CADASIL and obtain CADASIL-specific VSMCs and VECs. Using this model, Ling et al. identify clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease. The illustration depicts the Chinese historical allusions “King Yu Tamed the Flood”. King Yu managed to tame the flood (blood vessels) and earned a thriving kingdom to rule.
Professor Ju-Chi Li, one of the pioneers and founders of modern genetics in China
He Zhang
2019, 10(4): 235-237. doi: 10.1007/s13238-017-0487-2
Research Articles
Optic tectal superficial interneurons detect motion in larval zebrafish
Chen Yin, Xiaoquan Li, Jiulin Du
2019, 10(4): 238-248. doi: 10.1007/s13238-018-0587-7
Detection of moving objects is an essential skill for animals to hunt prey, recognize conspecifics and avoid predators. The zebrafish, as a vertebrate model, primarily uses its elaborate visual system to distinguish moving objects against background scenes. The optic tectum (OT) receives and integrates inputs from various types of retinal ganglion cells (RGCs), including direction-selective (DS) RGCs and size-selective RGCs, and is required for both prey capture and predator avoidance. However, it remains largely unknown how motion information is processed within the OT. Here we performed in vivo whole-cell recording and calcium imaging to investigate the role of superficial interneurons (SINs), a specific type of optic tectal neurons, in motion detection of larval zebrafish. SINs mainly receive excitatory synaptic inputs, exhibit transient ON-or OFF-type of responses evoked by light flashes, and possess a large receptive field (RF). One fifth of SINs are DS and classified into two subsets with separate preferred directions. Furthermore, SINs show size-dependent responses to moving dots. They are efficiently activated by moving objects but not static ones, capable of showing sustained responses to moving objects and having less visual adaptation than periventricular neurons (PVNs), the principal tectal cells. Behaviorally, ablation of SINs impairs prey capture, which requires local motion detection, but not global looming-evoked escape. Finally, starvation enhances the gain of SINs' motion responses while maintaining their size tuning and DS. These results indicate that SINs serve as a motion detector for sensing and localizing sized moving objects in the visual field.
Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells
Chen Ling, Zunpeng Liu, Moshi Song, Weiqi Zhang, Si Wang, Xiaoqian Liu, Shuai Ma, Shuhui Sun, Lina Fu, Qun Chu, Juan Carlos Izpisua Belmonte, Zhaoxia Wang, Jing Qu, Yun Yuan, Guang-Hui Liu
2019, 10(4): 249-271. doi: 10.1007/s13238-019-0608-1
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient's iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSCbased disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase
Jinbo Huang, Xu Dong, Zhou Gong, Ling-Yun Qin, Shuai Yang, Yue-Ling Zhu, Xiang Wang, Delin Zhang, Tingting Zou, Ping Yin, Chun Tang
2019, 10(4): 272-284. doi: 10.1007/s13238-018-0518-7
N6-methyladenosine (m6A), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without. The ZFD thus serves as the target recognition domain, a structural feature previously shown for DNA methyltransferases, and cooperates with the MTDs of METTL3-METTL14 for catalysis. However, the interaction between the ZFD and the specific RNA is extremely weak, with the binding affinity at several hundred micromolar under physiological conditions. The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel β-sheet. Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface. As a division of labor, the RNAbinding interface comprises basic residues from zinc finger 1 and hydrophobic residues from β-sheet and zinc finger 2. Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded, which may permit the cooperation between the two domains during catalysis. Together, the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA m6A modification.
Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter
Donghao Sun, Xuetao Cao, Chunmei Wang
2019, 10(4): 285-294. doi: 10.1007/s13238-018-0581-0
Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a nontraditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.
Effect of pH, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes
Yirui Cheng, Qingyu Zeng, Qing Han, Weiliang Xia
2019, 10(4): 295-299. doi: 10.1007/s13238-018-0529-4
TLE4 acts as a corepressor of Hes1 to inhibit inflammatory responses in macrophages
Xiang Zhang, Xiaoyu Li, Fei Ning, Yingli Shang, Xiaoyu Hu
2019, 10(4): 300-305. doi: 10.1007/s13238-018-0554-3
A unified deep-learning network to accurately segment insulin granules of different animal models imaged under different electron microscopy methodologies
Xiaoya Zhang, Xiaohong Peng, Chengsheng Han, Wenzhen Zhu, Lisi Wei, Yulin Zhang, Yi Wang, Xiuqin Zhang, Hao Tang, Jianshe Zhang, Xiaojun Xu, Fengping Feng, Yanhong Xue, Erlin Yao, Guangming Tan, Tao Xu, Liangyi Chen
2019, 10(4): 306-311. doi: 10.1007/s13238-018-0575-y