Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1.
Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1.
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DOI：
10.1038/s41467-022-30466-6
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发表时间：
2022-05-19
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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神经元活动正在成为中枢和周围神经系统癌症的驱动因素。在这里，我们检查了肿瘤易感综合征神经纤维瘤病-1 (NF1) 小鼠模型的神经元生理学，这些模型具有不同的发展神经系统癌症的倾向。我们发现，具有致瘤 Nf1 基因突变的小鼠的中枢和周围神经系统神经元表现出过度兴奋性，并且活性依赖性促肿瘤旁分泌因子的分泌增加。我们发现了一种由周围神经元以活性调节方式产生的神经纤维瘤丝裂原 (COL1A2)，它会增加 NF1 缺陷的雪旺细胞增殖，从而确定神经纤维瘤受到神经元活动的调节。相比之下，在缺乏神经纤维瘤或视神经胶质瘤的 NF1 患者中发现的具有 Arg1809Cys Nf1 突变的小鼠，不会表现出神经元过度兴奋或发展这些 NF1 相关肿瘤。易患肿瘤的 Nf1 突变神经元的过度兴奋是由于 NF1 调节的超极化激活的环核苷酸门控 (HCN) 通道功能降低所致，因此 HCN 通道激活可减弱神经元兴奋性、活性调节的旁分泌因子产生和肿瘤进展。总的来说，这些发现表明 NF1 突变在神经元水平发挥作用，通过增加神经元兴奋性和活性调节旁分泌因子的产生来改变肿瘤易感性。神经元活动正在成为神经系统肿瘤的驱动因素。在这里，作者在神经纤维瘤病-1 (NF1) 小鼠模型中证明，Nf1 突变通过降低超极化激活的环核苷酸门控 (HCN) 通道功能，差异性地驱动小鼠中枢神经系统和周围神经系统肿瘤的生长。
Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production. Neuronal activity is emerging as a driver of nervous system tumors. Here, the authors show in mouse models of Neurofibromatosis-1 (NF1) that Nf1 mutations differentially drive both central and peripheral nervous system tumor growth in mice through reduced hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function.
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影响因子：
11.2
作者：
Hegedus, Balazs;Banerjee, Debasish;Gutmann, David H.
通讯作者：
Gutmann, David H.
影响因子：
6.5
作者：
Atit, RP;Crowe, MJ;Ratner, N
通讯作者：
Ratner, N
影响因子：
11.2
作者：
Daginakatte, Girish C.;Gianino, Scott M.;Gutmann, David H.
通讯作者：
Gutmann, David H.
影响因子：
3.5
作者：
Anastasaki, Corina;Woo, Albert S.;Gutmann, David H.
通讯作者：
Gutmann, David H.
影响因子：
5.6
作者：
Campbell SL;Buckingham SC;Sontheimer H
通讯作者：
Sontheimer H