AbstractThe development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons.

摘要功能性神经元的发育是控制细胞增殖和分化的多种信号通路的复杂编排。因为抗氧化剂的平衡对于神经元的存活和发育很重要，所以我们假设必须抑制ferroptosis才能获得神经元。

We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C.

我们发现，去除抗氧化剂会减少神经元发育和皮质类器官的层状组织，当ferroptosis被ferrostatin-1抑制或在维生素A存在下发生神经元分化时，皮质类器官会完全恢复。此外，铁超负荷诱导C的发育生长缺陷。

elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids..

线虫被维生素E和A改善。我们确定全反式视黄酸激活视黄酸受体，其协调抗铁蛋白基因的表达。相反，视网膜和视黄醇显示出自由基捕获的抗氧化活性。总之，我们的研究揭示了维生素A在协调ferroptosis基本细胞守门人表达方面的意外功能，并证明了通过自由基捕获抗氧化剂或维生素A抑制ferroptosis是获得成熟神经元和皮质类器官中适当的层状组织所必需的。。

IntroductionDuring brain development, neurons arise in a tightly controlled process regulating an important balance between proliferation and differentiation events1. To ensure that cells emerge, migrate, and mature at the right time and space, a network of genetic and molecular factors is required2.

引言在大脑发育过程中，神经元在严格控制的过程中产生，调节增殖和分化事件之间的重要平衡1。为了确保细胞在正确的时间和空间出现，迁移和成熟，需要一个遗传和分子因素网络2。

However, the exact factors and their precise interplay are still not fully understood. Regulated cell death (RCD) eliminates half of the neurons initially generated during mammalian brain development and helps shape the organization of cortical circuits by regulating their cellular composition3,4. Apoptosis, a well-studied RCD modality, has so far been described as the major form of cell death during the developing nervous system3,4.Ferroptosis is another RCD, which occurs through iron-dependent lipid peroxidation5,6,7,8.

然而，确切的因素及其确切的相互作用仍不完全清楚。。细胞凋亡是一种经过充分研究的RCD方式，迄今为止被描述为发育中的神经系统中细胞死亡的主要形式3,4。Ferroptosis是另一种RCD，它通过铁依赖性脂质过氧化发生5,6,7,8。

It is controlled by a number of cellular gatekeepers, including the system-xc-/glutathione peroxidase 4 (GPX4)/glutathione axis7, the ferroptosis suppressor protein 1 (FSP1)/ubiquinol/vitamin K axis9,10,11, the GTP cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4)/dihydrofolate reductase (DHFR) axis12,13, and the nuclear receptor Farnesoid X receptor (FXR)14,15, amongst others.

它由许多细胞看门人控制，包括系统xc-/谷胱甘肽过氧化物酶4（GPX4）/谷胱甘肽轴7，铁浓化抑制蛋白1（FSP1）/泛醇/维生素K轴9,10,11，GTP环水解酶1（GCH1）/四氢生物蝶呤（BH4）/二氢叶酸还原酶（DHFR）轴12,13和核受体法尼醇X受体（FXR）14,15等。

Ferroptosis can be the cause of several degenerative diseases of the adult brain, heart, lung, and kidney7. However, our understanding of the functions of ferroptosis during brain development remains rudimentary. In this study, we illuminate the detrimental role of increased ferroptosis during neurogenesis and the necessity to inhibit ferroptosis by radical-trapping antioxidants or vitamin A to obtain cortical neurons.ResultsVitamin A restores neuronal differentiation in the absence of antioxidant protectionMost neuronal differentiation protocols require a series of antioxidants (AO.

Ferroptosis可能是成人大脑，心脏，肺和肾脏几种退行性疾病的原因7。然而，我们对大脑发育过程中ferroptosis功能的理解仍然是初步的。在这项研究中，我们阐明了神经发生过程中铁浓化增加的有害作用，以及通过自由基捕获抗氧化剂或维生素A来获得皮质神经元来抑制铁浓化的必要性。结果维生素A在没有抗氧化保护的情况下恢复神经元分化大多数神经元分化方案需要一系列抗氧化剂（AO）。

Data availability

数据可用性

All data are available in the article and its Supplementary Information. Western blot full scan images are shown in Supplementary Fig. 7. The RNAseq data (count data) generated in this study are provided in Supplementary Data 3. In addition, fastq files are deposited at NIH BioProject under the number PRJNA1115822. Source data are provided in this paper..

。蛋白质印迹全扫描图像显示在补充图7中。本研究中产生的RNAseq数据（计数数据）在补充数据3中提供。此外，fastq文件以编号PRJNA115822存放在NIH BioProject。本文提供了源数据。。

Code availability

代码可用性

The source code is available at https://github.com/MendenLab/DEx_StemCells_new.

源代码可在https://github.com/MendenLab/DEx_StemCells_new.

ReferencesGötz, M. & Huttner, W. B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777–788 (2005).Article

参考文献Götz，M。＆Huttner，W.B。神经发生的细胞生物学。Nat。Rev。Mol。Cell Biol。6777-788（2005）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Ninkovic, J. & Götz, M. Signaling in adult neurogenesis: from stem cell niche to neuronal networks. Curr. Opin. Neurobiol. 17, 338–344 (2007).Article

Ninkovic，J。＆Götz，M。成人神经发生中的信号传导：从干细胞生态位到神经元网络。货币。奥平。神经生物学。17338-344（2007）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Wong, F. K. & Marín, O. Developmental cell death in the cerebral cortex. Annu. Rev. Cell Dev. Biol. 35, 523–542 (2019).Article

Wong，F.K。＆Marín，O。大脑皮层发育细胞死亡。年。Rev.Cell Dev.Biol。35523-542（2019）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Yamaguchi, Y. & Miura, M. Programmed cell death in neurodevelopment. Dev. Cell 32, 478–490 (2015).Article

Yamaguchi，Y。＆Miura，M。神经发育中的程序性细胞死亡。Dev.Cell 32478-490（2015）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).Article

Dixon，S.J.等人，《铁浓化：一种铁依赖性的非凋亡细胞死亡形式》。细胞1491060-1072（2012）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hadian, K. & Stockwell, B. R. SnapShot: Ferroptosis. Cell 181, 1188–1188.e1181 (2020).Article

Hadian，K。和Stockwell，B.R。快照：Ferroptosis。细胞1811188-1188.e1181（2020）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Stockwell, B. R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).Article

Stockwell，B.R。Ferroptosis 10岁：新兴机制，生理功能和治疗应用。细胞1852401-2421（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hadian, K. & Stockwell, B. R. The therapeutic potential of targeting regulated non-apoptotic cell death. Nat. Rev. Drug Discov. (2023).Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).Article

Hadian，K。＆Stockwell，B.R。靶向调节性非凋亡细胞死亡的治疗潜力。《药物目录》修订版。（2023年）。Bersuker，K。等人。辅酶Q氧化还原酶FSP1与GPX4平行起作用以抑制铁浓化。。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).Article

Doll，S。等人，FSP1是一种不依赖谷胱甘肽的铁浓化抑制剂。自然575693-698（2019）。文章

ADS

广告

PubMed

PubMed

Google Scholar

谷歌学者

Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).Article

三岛，E。等人。非典型维生素K循环是一种有效的铁浓化抑制剂。自然608778-783（2022）。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kraft, V. A. N. et al. GTP Cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).Article

Kraft，V.A.N.等人，GTP环水解酶1/四氢生物蝶呤通过脂质重塑抵消铁浓化。ACS分。科学。6，41-53（2020）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Soula, M. et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol. 16, 1351–1360 (2020).Article

Soula，M.等人。癌细胞对经典铁浓化诱导剂敏感性的代谢决定因素。自然化学。生物学161351-1360（2020）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kim, D. H. et al. Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes. Redox Biol. 54, 102382 (2022).Article

Kim，D.H.等人，法尼醇X受体通过调节铁浓化相关基因的转录来预防顺铂诱导的急性肾损伤。氧化还原生物。54102382（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Tschuck, J. et al. Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis. Nat. Commun. 14, 6908 (2023).Article

Tschuck，J。等人。胆汁酸激活法尼醇X受体可抑制脂质过氧化和铁浓化。国家公社。146908（2023）。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Qi, Y. et al. Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells. Nat. Biotechnol. 35, 154–163 (2017).Article

Qi，Y.等人联合小分子抑制加速了人多能干细胞功能性皮质神经元的衍生。美国国家生物技术公司。35154-163（2017）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Maroof, A. M. et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559–572 (2013).Article

Maroof，A.M.等人指导人类胚胎干细胞皮质中间神经元的分化和功能成熟。细胞干细胞12559-572（2013）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Padmanabhan Nair, V. et al. Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3. Cell Stem Cell 28, 1566–1581.e1568 (2021).Article

Padmanabhan Nair，V。等人。HERV-K（HML-2）的激活通过增加NTRK3破坏皮质模式和神经元分化。细胞干细胞281566–1581.e1568（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Iturbide, A. et al. Retinoic acid signaling is critical during the totipotency window in early mammalian development. Nat. Struct. Mol. Biol. 28, 521–532 (2021).Article

。自然结构。分子生物学。28521-532（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rhinn, M. & Dollé, P. Retinoic acid signalling during development. Development 139, 843–858 (2012).Article

Rhinn，M。＆Dollé，P。发育过程中的视黄酸信号传导。发展139843-858（2012）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Huang, P., Chandra, V. & Rastinejad, F. Retinoic acid actions through mammalian nuclear receptors. Chem. Rev. 114, 233–254 (2014).Article

Huang，P.，Chandra，V。和Rastinejad，F。视黄酸通过哺乳动物核受体的作用。化学。版本114233–254（2014）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Amengual, J. et al. Two carotenoid oxygenases contribute to mammalian provitamin A metabolism. J. Biol. Chem. 288, 34081–34096 (2013).Article

Amengual，J。等人。两种类胡萝卜素加氧酶有助于哺乳动物的维生素原A代谢。J、 生物。化学。28834081-34096（2013）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Feng, H. et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 30, 3411–3423.e3417 (2020).Article

Feng，H。等人。转铁蛋白受体是一种特定的铁浓化标志物。Cell Rep.303411–3423.e3417（2020）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jin, J. et al. Machine learning classifies ferroptosis and apoptosis cell death modalities with TfR1 immunostaining. ACS Chem. Biol. 17, 654–660 (2022).Article

Jin，J。等人。机器学习用TfR1免疫染色对ferroptosis和凋亡细胞死亡模式进行分类。ACS化学。生物学17654-660（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Buchsbaum, I. Y. et al. ECE2 regulates neurogenesis and neuronal migration during human cortical development. EMBO Rep. 21, e48204 (2020).Article

Buchsbaum，I.Y.等人，ECE2在人类皮层发育过程中调节神经发生和神经元迁移。EMBO Rep.21，e48204（2020）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mann, J. et al. Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury. Cell Chem. Biol. 31, 249–264.e247 (2024).Article

Mann，J。等人。油酸抑制铁下垂可减轻铁超负荷引起的损伤。细胞化学。生物学31249–264.e247（2024）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Kiser, P. D., Golczak, M. & Palczewski, K. Chemistry of the retinoid (visual) cycle. Chem. Rev. 114, 194–232 (2014).Article

Kiser，P.D.，Golczak，M。和Palczewski，K。类维生素A（视觉）循环的化学。化学。版本114194–232（2014）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Barber, K., Studer, L. & Fattahi, F. Derivation of enteric neuron lineages from human pluripotent stem cells. Nat. Protoc. 14, 1261–1279 (2019).Article

Barber，K.，Studer，L。＆Fattahi，F。从人多能干细胞衍生肠神经元谱系。自然协议。141261-1279（2019）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Tchieu, J. et al. A modular platform for differentiation of human PSCs into all major ectodermal lineages. Cell Stem Cell 21, 399–410.e397 (2017).Article

Tchieu，J。等人。用于将人类PSC分化为所有主要外胚层谱系的模块化平台。细胞干细胞21399-410.e397（2017）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Fattahi, F. et al. Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease. Nature 531, 105–109 (2016).Article

Fattahi，F.等人。推导人类ENS谱系，用于先天性巨结肠的细胞治疗和药物发现。自然531105-109（2016）。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kim, T. W. et al. Biphasic activation of WNT signaling facilitates the derivation of midbrain dopamine neurons from hESCs for translational use. Cell Stem Cell 28, 343–355.e345 (2021).Article

Kim，T.W.等人。WNT信号的双相激活有助于从hESC衍生中脑多巴胺神经元用于翻译用途。细胞干细胞28343–355.e345（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zeng, W. et al. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci. Rep. 5, 11100 (2015).Article

Zeng，W。等人。抗氧化剂治疗增强了急性肝衰竭模型中人间充质干细胞的抗应激能力和治疗效果。科学。Rep.511100（2015）。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Calvo-Garrido, J. et al. Protocol for the derivation, culturing, and differentiation of human iPS-cell-derived neuroepithelial stem cells to study neural differentiation in vitro. STAR Protoc. 2, 100528 (2021).Article

Calvo Garrido，J.等人。人iPS细胞衍生的神经上皮干细胞的衍生，培养和分化方案，以研究体外神经分化。恒星质子。2100 528（2021）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Chui, A., Zhang, Q., Dai, Q. & Shi, S. H. Oxidative stress regulates progenitor behavior and cortical neurogenesis. Development 147, https://doi.org/10.1242/dev.184150 (2020).Levings, D. C., Pathak, S. S., Yang, Y. M. & Slattery, M. Limited expression of Nrf2 in neurons across the central nervous system.

Chui，A.，Zhang，Q.，Dai，Q。＆Shi，S.H。氧化应激调节祖细胞行为和皮质神经发生。发展147，https://doi.org/10.1242/dev.184150。Levings，D.C.，Pathak，S.S.，Yang，Y.M。＆Slattery，M。Nrf2在整个中枢神经系统的神经元中的表达有限。

Redox Biol. 65, 102830 (2023).Article .

氧化还原生物。65102830（2023）。文章。

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Head, B., La Du, J., Tanguay, R. L., Kioussi, C. & Traber, M. G. Vitamin E is necessary for zebrafish nervous system development. Sci. Rep. 10, 15028 (2020).Article

Head，B.，La Du，J.，Tanguay，R.L.，Kioussi，C。＆Traber，M.G。维生素E是斑马鱼神经系统发育所必需的。科学。代表1015028（2020）。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

McDougall, M., Choi, J., Truong, L., Tanguay, R. & Traber, M. G. Vitamin E deficiency during embryogenesis in zebrafish causes lasting metabolic and cognitive impairments despite refeeding adequate diets. Free Radic. Biol. Med. 110, 250–260 (2017).Article

McDougall，M.，Choi，J.，Truong，L.，Tanguay，R。＆Traber，M.G。斑马鱼胚胎发生过程中维生素E缺乏会导致持续的代谢和认知障碍，尽管重新喂食了足够的饮食。自由基。生物学杂志110250-260（2017）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Deluao, J. C. et al. OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: Reactive oxygen species in the mammalian pre-implantation embryo. Reproduction 164, F95–F108 (2022).Article

Deluao，J.C.等人，《氧化应激与生殖功能：哺乳动物植入前胚胎中的活性氧》。复制164，F95–F108（2022）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Lane, M. A. & Bailey, S. J. Role of retinoid signalling in the adult brain. Prog. Neurobiol. 75, 275–293 (2005).Article

Lane，M.A。和Bailey，S.J。类维生素A信号在成人大脑中的作用。程序。神经生物学。75275-293（2005）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Maden, M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat. Rev. Neurosci. 8, 755–765 (2007).Article

Maden，M。视黄酸在神经系统的发育，再生和维持中的作用。神经科学杂志。。文章

PubMed

PubMed

Google Scholar

谷歌学者

Janesick, A., Wu, S. C. & Blumberg, B. Retinoic acid signaling and neuronal differentiation. Cell Mol. Life Sci. 72, 1559–1576 (2015).Article

Janesick，A.，Wu，S.C。＆Blumberg，B。视黄酸信号传导和神经元分化。细胞分子生命科学。721559-1576（2015）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ghyselinck, N. B. & Duester, G. Retinoic acid signaling pathways. Development 146, https://doi.org/10.1242/dev.167502 (2019).Blaner, W. S., Shmarakov, I. O. & Traber, M. G. Vitamin A and Vitamin E: Will the real antioxidant please stand up? Annu. Rev. Nutr. 41, 105–131 (2021).Article .

Ghyselinck，N.B。和Duester，G。视黄酸信号通路。发展146，https://doi.org/10.1242/dev.167502（2019年）。维生素A和维生素E：真正的抗氧化剂能站起来吗？年。修订版Nutr。41105-131（2021）。文章。

PubMed

PubMed

Google Scholar

谷歌学者

Bi, G. et al. Retinol saturase mediates retinoid metabolism to impair a ferroptosis defense system in cancer cells. Cancer Res. 83, 2387–2404 (2023).Article

Bi，G。等人。视黄醇饱和酶介导类视黄醇代谢，损害癌细胞的铁浓化防御系统。癌症研究832387-2404（2023）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Jakaria, M., Belaidi, A. A., Bush, A. I. & Ayton, S. Vitamin A metabolites inhibit ferroptosis. Biomed. Pharmacother. 164, 114930 (2023).Article

Jakaria，M.，Belaidi，A.A.，Bush，A.I。＆Ayton，S。维生素A代谢物抑制铁浓化。生物医学。药剂师。164114930（2023）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408 (2001).Article

Livak，K.J。＆Schmittgen，T.D。使用实时定量PCR和2（-Delta Delta C（T））方法分析相对基因表达数据。方法25402-408（2001）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).Article

Pfaffl，M.W。实时RT-PCR中相对定量的新数学模型。核酸研究29，e45（2001）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480, 547–551 (2011).Article

。自然480547-551（2011）。文章

ADS

广告

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).Article

Love，M.I.，Huber，W。＆Anders，S。用DESeq2缓和了RNA-seq数据的倍数变化和分散估计。基因组生物学。。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhou, T. et al. High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain. Cell Stem Cell 21, 274–283.e275 (2017).Article

Zhou，T。等人。hPSC神经祖细胞的高含量筛选确定了抑制胎儿样器官和成人大脑中寨卡病毒感染的候选药物。细胞干细胞21274-283.e275（2017）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rueden, C. T. et al. ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinformatics 18, 529 (2017).Article

Rueden，C.T.等人。ImageJ2：下一代科学图像数据的ImageJ。BMC生物信息学18529（2017）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).Article

Schindelin，J。等人。斐济：生物图像分析的开源平台。《自然方法》9676-682（2012）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe thank Lena Klepper and Stefanie Brandner for their excellent technical assistance. The authors thank Milou Meeuse and Helge Großhans for gifting the unpublished strain HW2668. M.V. was funded by the Deutsche Forschungsgemeinschaft (RTG2668 – project number 435874434, Sachbeihilfe – project number 496872373, Sachbeihilfe – project number 498956525, and Sachbeihilfe – project number 497803923).FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthor notesJason TchieuPresent address: UC Department of Pediatrics, Division of Developmental Biology, Cincinnati Children’s Hospital Medical, Cincinnati, OH, USAThese authors contributed equally: Juliane Tschuck, Vidya Padmanabhan Nair.These authors jointly supervised this work: Michelle Vincendeau, Kamyar Hadian.Authors and AffiliationsResearch Unit Signaling and Translation, Helmholtz Zentrum München, Neuherberg, GermanyJuliane Tschuck, Ina Rothenaigner & Kamyar HadianEndogenous Retrovirus Group, Institute of Virology, Helmholtz Zentrum München, Neuherberg, GermanyVidya Padmanabhan Nair, Hin-Man Tai & Michelle VincendeauComputational Health Center, Helmholtz Zentrum München, Neuherberg, GermanyAna Galhoz & Michael P.

下载参考文献致谢我们感谢Lena Klepper和Stefanie Brandner提供的出色技术帮助。作者感谢Milou Meeuse和Helge Großhans赠送未发表的HW2668菌株。M、 V.由Deutsche Forschungsgemeinschaft（RTG2668–项目编号435874434，Sachbeihilfe–项目编号496872373，Sachbeihilfe–项目编号498956525和Sachbeihilfe–项目编号497803923）资助。资金开放获取资金由Projekt交易启用和组织。作者信息作者注释Cason TchieuPresent地址：美国俄亥俄州辛辛那提市辛辛那提儿童医院医学部发育生物学系加州大学儿科这些作者做出了同样的贡献：Juliane Tschuck，Vidya Padmanabhan Nair。这些作者共同监督了这项工作：Michelle Vincendeau，Kamyar Hadian。作者和附属机构研究单位信号与翻译，亥姆霍兹-岑特鲁姆慕尼黑，纽赫伯格，德国朱利安·丘克，Ina Rothenaigner＆Kamyar-Hadianegenous逆转录病毒组，病毒学研究所，亥姆霍兹-岑特鲁姆慕尼黑，纽赫伯格，GermanyVidya Padmanabhan Nair，Hin Man Tai＆Michelle Vincendeau计算健康中心，亥姆霍兹-岑特鲁姆慕尼黑，纽赫伯格，GermanyAna Galhoz＆Michael P。

MendenDepartment of Biology, Ludwig-Maximilians University Munich, Munich, GermanyAna GalhozInstitute of Functional Epigenetics, Helmholtz Zentrum München, Neuherberg, GermanyCarole Zaratiegui & Daphne S. CabiancaDevelopmental Biology and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USAGabriele Ciceri, Jason Tchieu & Lorenz StuderDepartment of Biological Sciences, Department of Chemistry, Herbert Irving Comprehensive Cancer Center, Irving Institute for Cancer Dynamics, Columbia University, Ne.

慕尼黑路德维希·马克西米利安大学生物学系，德国功能表观遗传学研究所，亥姆霍兹-岑特鲁姆-慕尼黑，纽赫伯格，德国卡罗尔·扎拉提吉和达芙妮·S·卡比安发展生物学和干细胞生物学中心，纪念斯隆·凯特琳癌症中心，纽约，纽约，USAGabriele Ciceri，Jason Tchieu＆Lorenz StuderDepartment of Biologics，Department of Chemistry，Herbert Irving Comprehensive Cancer Center，欧文癌症动力学研究所，哥伦比亚大学，Ne。

PubMed Google ScholarVidya Padmanabhan NairView author publicationsYou can also search for this author in

PubMed Google ScholarVidya Padmanabhan NairView作者出版物您也可以在

PubMed Google ScholarAna GalhozView author publicationsYou can also search for this author in

PubMed Google ScholarAna GalhozView作者出版物您也可以在

PubMed Google ScholarCarole ZaratieguiView author publicationsYou can also search for this author in

PubMed Google ScholarCarole ZaratieguiView作者出版物您也可以在

PubMed Google ScholarHin-Man TaiView author publicationsYou can also search for this author in

PubMed Google ScholarHin Man TaiView作者出版物您也可以在

PubMed Google ScholarGabriele CiceriView author publicationsYou can also search for this author in

PubMed Google ScholarGabriele CiceriView作者出版物您也可以在

PubMed Google ScholarIna RothenaignerView author publicationsYou can also search for this author in

PubMed Google ScholarIna RothenaignerView作者出版物您也可以在

PubMed Google ScholarJason TchieuView author publicationsYou can also search for this author in

PubMed谷歌学者Jason TchieuView作者出版物您也可以在

PubMed Google ScholarBrent R. StockwellView author publicationsYou can also search for this author in

PubMed Google ScholarBrent R.StockwellView作者出版物您也可以在

PubMed Google ScholarLorenz StuderView author publicationsYou can also search for this author in

PubMed Google ScholarLorenz StuderView作者出版物您也可以在

PubMed Google ScholarDaphne S. CabiancaView author publicationsYou can also search for this author in

PubMed Google ScholarDaphne S.CabiancaView作者出版物您也可以在

PubMed Google ScholarMichael P. MendenView author publicationsYou can also search for this author in

PubMed Google Scholarmamichael P.MendenView作者出版物您也可以在

PubMed Google ScholarMichelle VincendeauView author publicationsYou can also search for this author in

PubMed谷歌ScholarMichelle VincendeauView作者出版物您也可以在

PubMed Google ScholarKamyar HadianView author publicationsYou can also search for this author in

PubMed Google ScholarContributionsK.H. and M.V. conceptualized, designed, and generally supervised the study; J.T., I.R. and K.H. performed, analyzed, and interpreted the experiments in HT-1080 cells; V.P.N., G.C., J.Tch., H.M.T. and M.V. performed, analyzed and interpreted the stem cell experiments; C.Z.

PubMed谷歌学术贡献SK。H、 和M.V.对研究进行了概念化，设计和一般监督；J、 T.，I.R.和K.H.在HT-1080细胞中进行，分析和解释了实验；五、 P.N.，G.C.，J.Tch。，H、 M.T.和M.V.进行，分析和解释了干细胞实验；C、 Z。

performed the C. elegans in vivo experiments and analyzed and interpreted the data with support from D.S.C., A.G. and M.P.M. analyzed and interpreted the RNAseq data; B.R.S., L.S., D.S.C., M.P.M., M.V., and K.H. supervised individual experiments; J.T., V.P.N., M.V. and K.H. wrote the original draft; J.T., V.P.N., M.V.

进行了秀丽隐杆线虫体内实验，并在D.S.C.，A.G.和M.P.M.的支持下分析和解释了数据。分析和解释了RNAseq数据；B、 R.S.，L.S.，D.S.C.，M.P.M.，M.V。和K.H.监督个体实验；J、 T.，V.P.N.，M.V.和K.H.撰写了原始草案；J、 T.，V.P.N.，M.V。

and K.H. edited the manuscript; all authors read, commented and approved the manuscript for submission.Corresponding authorsCorrespondence to.

和K.H.编辑了手稿；所有作者都阅读，评论并批准了稿件的提交。。

Michelle Vincendeau or Kamyar Hadian.Ethics declarations

Michelle Vincendeau或Kamyar Hadian。道德宣言

Competing interests

相互竞争的利益

B.R.S. is an inventor on patents (granted) and patent applications (pending) involving ferroptosis; co-founded and serves as a consultant to ProJenX, Inc. and Exarta Therapeutics; holds equity in Sonata Therapeutics; serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP; and receives sponsored research support from Sumitomo Dainippon Pharma Oncology.

B、 R.S.是涉及ferroptosis的专利（已授予）和专利申请（待决）的发明人；共同创立并担任ProJenX，Inc.和Exarta Therapeutics的顾问；持有Sonata Therapeutics的股权；担任Weatherwax Biotechnologies Corporation和Akin Gump Strauss Hauer＆Feld LLP的顾问；并获得住友大尼邦制药肿瘤学的赞助研究支持。

L.S. is a scientific founder and paid consultant of BlueRock Therapeutics, a scientific founder of DaCapo Brain Science, and an inventor on patents (granted) owned by MSKCC on the differentiation of human pluripotent stem cells into specific neurons. J.T. and K.H. are inventors on a patent application (pending) involving ferroptosis.

五十、 S.是BlueRock Therapeutics的科学创始人和付费顾问，是DaCapo Brain Science的科学创始人，也是MSKCC拥有的人类多能干细胞分化为特定神经元专利的发明人。J、 T.和K.H.是涉及ferroptosis的专利申请（未决）的发明人。

The remaining authors declare no competing interests..

其余作者声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Nature Communications感谢匿名审稿人对这项工作的同行评审做出的贡献。可以获得同行评审文件。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1Supplementary Data 2Supplementary Data 3Reporting SummarySource dataSource dataRights and permissions.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息同行评审文件其他补充文件的描述补充数据1补充数据2补充数据3报告摘要源数据源数据权限。

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可证中，并且您的预期用途未被法律法规允许或超出允许的用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleTschuck, J., Padmanabhan Nair, V., Galhoz, A. et al. Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development.

转载和许可本文引用本文Chuck，J.，Padmanabhan Nair，V.，Galhoz，A。等人。通过维生素A或自由基捕获抗氧化剂抑制铁浓化对于神经元发育至关重要。

Nat Commun 15, 7611 (2024). https://doi.org/10.1038/s41467-024-51996-1Download citationReceived: 16 August 2023Accepted: 22 August 2024Published: 01 September 2024DOI: https://doi.org/10.1038/s41467-024-51996-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157611（2024）。https://doi.org/10.1038/s41467-024-51996-1Download引文收到日期：2023年8月16日接受日期：2024年8月22日发布日期：2024年9月1日OI：https://doi.org/10.1038/s41467-024-51996-1Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供

CommentsBy submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

评论通过提交评论，您同意遵守我们的条款和社区指南。如果您发现有虐待行为或不符合我们的条款或准则，请将其标记为不合适。