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2021 Vol. 12, No. 8

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The enteric nervous system (ENS) is indispensable for normal functions of the gastrointestinal tract. In this issue, Sun et al. exploited the advanced 3D imaging technique to visualize the mouse, non-human primate, and human ENS. The cover image showed the whole-tissue co-immunolabeling of tyrosine hydroxylase for catecholaminergic axons (green) and vesicular acetylcholine transporter for cholinergic axons (red) within the mouse ENS. This study observed the profound loss of catecholaminergic axons in the human and mouse colons during colitis. Notably, this neurodegenerative event decreased the local content of the neurotransmitter norepinephrine that would otherwise promote expression of pro-inflammatory IL-17 cytokines. Therefore, this study revealed the unique, beneficial role of neurodegeneration within the ENS to protect against the colon inflammation.

Recollection
Kuo-Hua Sun: The founder of physiologic psychology and child psychology in China
Yimeng Wang, Yanyan Qian
2021, 12(8): 593-595. doi: 10.1007/s13238-019-00666-w
[Abstract](632) [PDF 343KB](17)
Abstract:
Hightlight
A good gut feeling on Sarm1-mediated axon degeneration
Victoria E. von Saucken, David J. Simon
2021, 12(8): 596-598. doi: 10.1007/s13238-021-00842-x
[Abstract](462) [PDF 126KB](17)
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Review
Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy
Pranavi Koppula, Li Zhuang, Boyi Gan
2021, 12(8): 599-620. doi: 10.1007/s13238-020-00789-5
[Abstract](2127) [PDF 2253KB](164)
Abstract:
The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucoseand glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.
Research Articles
Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon
Yue Sun, Qi Wang, Yi Wang, Wenran Ren, Ying Cao, Jiali Li, Xin Zhou, Wei Fu, Jing Yang
2021, 12(8): 621-638. doi: 10.1007/s13238-021-00835-w
[Abstract](892) [PDF 3733KB](110)
Abstract:
Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, nonhuman primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.
Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2
Xiaoying Chen, Xu Han, Bruno Blanchi, Wuqiang Guan, Weihong Ge, Yong-Chun Yu, Yi E. Sun
2021, 12(8): 639-652. doi: 10.1007/s13238-020-00773-z
[Abstract](742) [PDF 2581KB](39)
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Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2- deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development.
Letters
OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients
Jun Liu, Junchen Chen, Yadan Zhong, Xiaoling Yu, Ping Lu, Jianqi Feng, Xin Zhang, Shufeng Ma, Chao Yang, Bin Yang, Zhili Rong
2021, 12(8): 653-661. doi: 10.1007/s13238-020-00818-3
[Abstract](460) [PDF 2008KB](66)
Abstract:
Structural insights into the activation initiation of full-length mGlu1
Jinyi Zhang, Lu Qu, Lijie Wu, Xiaomeng Tang, Feng Luo, Weixiu Xu, Yueming Xu, Zhi-Jie Liu, Tian Hua
2021, 12(8): 662-667. doi: 10.1007/s13238-020-00808-5
[Abstract](535) [PDF 967KB](60)
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Correction to: MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1
Mingxu Song, Yuan Yin, Jiwei Zhang, Binbin Zhang, Zehua Bian, Chao Quan, Leyuan Zhou, Yaling Hu, Qifeng Wang, Shujuan Ni, Bojian Fei, Weili Wang, Xiang Du, Dong Hua, Zhaohui Huang
2021, 12(8): 668-670. doi: 10.1007/s13238-021-00826-x
[Abstract](334) [PDF 712KB](13)
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