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Unraveling the intricate link between cell death and neuroinflammation using Drosophila as a model. 以果蝇为模型,揭示细胞死亡与神经炎症之间错综复杂的联系。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1479864
Pooja Rai, Andreas Bergmann

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in Drosophila. Mutations in the SNCA gene that encodes the alpha (α)-Synuclein protein have been linked to familial Parkinson's disease, disrupting autophagy regulation in neuronal cells and promoting the formation of Lewy bodies, a hallmark of Parkinson's pathology. This results in the loss of dopaminergic neurons, manifesting as movement disorders. α-Synuclein aggregation triggers innate immune responses by activating microglial cells, leading to phagocytic activity and the expression of neuroprotective antimicrobial peptides (AMPs). However, sustained AMP expression or chronic inflammation resulting from inadequate microglial phagocytosis can induce neuronal toxicity and apoptosis, leading to severe dopaminergic neuron loss. This review underscores the mechanistic connection between immune response pathways and α-Synuclein-mediated neurodegeneration using Drosophila models. Furthermore, we extensively explore factors influencing neuroinflammation and key immune signaling pathways implicated in neurodegenerative diseases, particularly Parkinson's disease. Given the limited success of traditional treatments, recent research has focused on therapies targeting inflammatory signaling pathways. Some of these approaches have shown promising results in animal models and clinical trials. We provide an overview of current therapeutic strategies showing potential in treating neurodegenerative diseases, offering new avenues for future research and treatment development.

蛋白质聚集是神经退行性疾病中常见的病理现象。这通常会导致神经炎症,从而加剧帕金森病和阿尔茨海默病等疾病的聚集和进展。在这里,我们重点研究果蝇帕金森病模型中的免疫反应和神经毒性。编码α(α)-突触核蛋白的SNCA基因突变与家族性帕金森病有关,这种突变破坏了神经细胞的自噬调节,促进了路易体的形成,而路易体正是帕金森病的病理特征。α-突触核蛋白的聚集会激活小胶质细胞,从而引发先天性免疫反应,导致吞噬细胞活性和神经保护性抗菌肽(AMPs)的表达。然而,持续的 AMP 表达或小胶质细胞吞噬功能不足导致的慢性炎症可诱发神经元毒性和凋亡,从而导致多巴胺能神经元的严重损失。本综述利用果蝇模型强调了免疫反应途径与α-突触核蛋白介导的神经变性之间的机理联系。此外,我们还广泛探讨了影响神经炎症的因素以及与神经退行性疾病(尤其是帕金森病)有关的关键免疫信号通路。鉴于传统疗法的成功率有限,最近的研究集中在针对炎症信号通路的疗法上。其中一些方法已在动物模型和临床试验中显示出良好的效果。我们概述了目前在治疗神经退行性疾病方面显示出潜力的治疗策略,为未来的研究和治疗开发提供了新的途径。
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引用次数: 0
Linking DNA damage and senescence to gestation period and lifespan in placental mammals. 将 DNA 损伤和衰老与胎盘哺乳动物的妊娠期和寿命联系起来。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1480695
Vijay Pratap Singh, Pushpendra Singh

The mechanism that synchronizes the timing of parturition remains a mystery. Each mammalian species has a specific duration of gestation that is determined by integrated interactions among the mother, placenta, and fetus. Senescence is primarily driven by DNA damage and is one of the critical factors influencing both parturition and lifespan. In this study, we investigated senescence as a physiological process during pregnancy and observed a gradual physiological increase in senescence in the maternal decidua and placental cells with gestation. This increase in senescence was associated with a gradual physiological increase in DNA damage during gestation. An analysis of the AnAge dataset revealed a positive correlation between the gestation period and maximum lifespan across 740 mammalian species. This finding supports the hypothesis that the rates of DNA damage and senescence may impact both the gestation period and lifespan. We suggest that the relationship between gestation period and lifespan in mammals is mediated by species-specific rates of DNA damage and senescence, necessitating further explorations into their causal roles.

使分娩时间同步的机制仍然是一个谜。每种哺乳动物都有特定的妊娠期,这是由母体、胎盘和胎儿之间的综合相互作用决定的。衰老主要由 DNA 损伤驱动,是影响分娩和寿命的关键因素之一。在这项研究中,我们将衰老作为孕期的一个生理过程进行了研究,并观察到母体蜕膜和胎盘细胞的衰老随着妊娠而逐渐增加。衰老的增加与妊娠期 DNA 损伤的逐渐增加有关。对 AnAge 数据集的分析表明,在 740 种哺乳动物中,妊娠期与最长寿命呈正相关。这一发现支持了 DNA 损伤率和衰老率可能同时影响妊娠期和寿命的假设。我们认为哺乳动物的妊娠期和寿命之间的关系是由特定物种的DNA损伤率和衰老率介导的,因此有必要进一步探索它们的因果作用。
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引用次数: 0
Obesity may impair response to ovarian stimulation. A retrospective observational study on oocyte quality. 肥胖可能会影响卵巢刺激反应。一项关于卵母细胞质量的回顾性观察研究。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1461132
Irene Iavarone, Daniela Mele, Francesca Caprio, Giada Andreoli, Maria Giovanna Vastarella, Pasquale de Franciscis, Carlo Ronsini

Background: Ovulatory dysfunction is more common in women with obesity. Body fat distribution is also crucial because anovulatory women have a greater waist circumference and more abdominal fat than ovulatory women of similar BMI. The primary aim of the present study is to determine whether there is a relationship between BMI and reproductive characteristics, including hormonal values, antral follicle count (AFC), endometrial assessment at transvaginal ultrasound evaluation (TVUS) during controlled ovarian stimulation (COS), and oocyte retrieval after Ovum Pick-Up (OPU).

Methods: Data from a cohort of 183 patients were analyzed and divided into three groups based on weight status: normal weight, overweight, and obesity. Evaluated reproductive characteristics included: age, basal values of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17-beta-estradiol (E2), thyroid stimulating hormone (TSH), anti-müllerian hormone (AMH), antral-follicle-count (AFC), duration of COS, E2, and progesterone at the last monitoring, TVUS endometrial thickness at the last monitoring before OPU, FOI after OPU. Additionally, the number of meiosis II oocytes retrieved (MII), the total dose of FSH administered, the ratio between MII and total FSH administered, and OSI were registered.

Results: AMH levels were significantly lower in obese patients compared to normal weight and overweight women (1.05 IQR 1.20, 1.58 IQR 2.16, 1.32 IQR 1.38, respectively, p-value = 0.032). When looking at the MII/FSH ratio, the normal weight group showed a median value of 3.3 with an IQR of 4.0, the overweight group showed a median value of 2.3 with an IQR of 1.9, and the obese group had a median value of 2.6 with an IQR of 2.8. Those data were statistically significant (p-value = 0.049).

Conclusion: These results emphasize the importance of considering weight status in fertility assessment and treatment planning.

背景:排卵功能障碍在肥胖女性中更为常见。身体脂肪分布也至关重要,因为与体重指数相似的排卵期妇女相比,无排卵妇女的腰围更大,腹部脂肪更多。本研究的主要目的是确定体重指数与生殖特征之间是否存在关系,包括激素值、前卵泡计数(AFC)、控制性卵巢刺激(COS)期间经阴道超声评估(TVUS)的子宫内膜评估以及取卵(OPU)后的卵母细胞检索:对 183 名患者的数据进行了分析,并根据体重状况分为三组:正常体重组、超重组和肥胖组。评估的生殖特征包括:年龄、卵泡刺激素(FSH)、黄体生成素(LH)、17-beta-雌二醇(E2)、促甲状腺激素(TSH)、抗苗勒氏激素(AMH)的基础值、前卵泡数(AFC)、COS持续时间、上次监测的E2和孕酮、OPU前最后一次监测的TVUS子宫内膜厚度、OPU后的FOI。此外,还记录了减数第二次分裂取卵数(MII)、FSH总剂量、MII与FSH总剂量之比以及OSI:与正常体重和超重妇女相比,肥胖患者的 AMH 水平明显较低(分别为 1.05 IQR 1.20、1.58 IQR 2.16、1.32 IQR 1.38,P 值 = 0.032)。在观察 MII/FSH 比率时,正常体重组的中位值为 3.3,IQR 为 4.0;超重组的中位值为 2.3,IQR 为 1.9;肥胖组的中位值为 2.6,IQR 为 2.8。这些数据具有统计学意义(P 值 = 0.049):这些结果强调了在生育评估和治疗计划中考虑体重状况的重要性。
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引用次数: 0
A dynamically loaded ex vivo model to study neocartilage and integration in human cartilage repair. 研究人体软骨修复中新软骨和整合的动态加载体外模型。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1449015
Anna Trengove, Lilith M Caballero Aguilar, Claudia Di Bella, Carmine Onofrillo, Serena Duchi, Andrea J O'Connor

Articular cartilage injuries in the knee can lead to post-traumatic osteoarthritis if untreated, causing debilitating problems later in life. Standard surgical treatments fail to ensure long lasting repair of damaged cartilage, often resulting in fibrotic tissue. While there is a vast amount of research into cartilage regeneration, integrating engineered implants with cartilage remains a challenge. As cartilage is a load bearing tissue, it is imperative to evaluate tissue repair strategies and their ability to integrate under mechanical loading. This work established a dynamically loaded ex vivo model of cartilage repair using human cartilage explants. The model was used to assess the efficacy of a stem cell therapy delivered in a bioadhesive hydrogel comprised of photocrosslinkable gelatin methacryloyl (GelMA) and microbial transglutaminase to repair the model defect. Extensive neocartilage production and integration were observed via histology and immunohistochemistry after 28 days chondrogenic culture. Analysis of culture media allowed monitoring of glycosaminoglycan and type II collagen production over time. A mechanical assessment of integration via a push out test showed a 15-fold increase in push out strength over the culture duration. The model was successful in exhibiting robust chondrogenesis with transglutaminase or without, and under both culture conditions. The work also highlights several limitations of ex vivo models and challenges of working with bioreactors that must be overcome to increase their utility. This ex vivo model has the potential to delay the need for costly pre-clinical studies and provide a more nuanced assessment of cartilage repair strategies than is possible in vivo.

膝关节软骨损伤如不及时治疗,可能会导致创伤后骨关节炎,给患者日后的生活带来严重影响。标准的手术治疗无法确保对受损软骨进行长期持久的修复,往往会导致纤维组织的形成。虽然对软骨再生进行了大量研究,但将工程植入物与软骨结合仍是一项挑战。软骨是一种承重组织,因此必须评估组织修复策略及其在机械负荷下的整合能力。这项研究利用人体软骨外植体建立了动态加载的软骨修复体外模型。该模型用于评估干细胞疗法在由光交联甲基丙烯酰明胶(GelMA)和微生物转谷氨酰胺酶组成的生物粘性水凝胶中的疗效,以修复模型缺损。经过 28 天的软骨培养后,通过组织学和免疫组化观察到了广泛的新软骨生成和整合。通过对培养基的分析,可以监测糖胺聚糖和 II 型胶原蛋白随时间推移的生成情况。通过推出试验对整合进行的力学评估显示,在培养期间,推出强度增加了 15 倍。无论是否使用转谷氨酰胺酶,在两种培养条件下,该模型都能成功地表现出稳健的软骨生成。这项工作还强调了体内外模型的一些局限性以及使用生物反应器工作所面临的挑战,要提高这些模型的实用性,就必须克服这些挑战。这种体外模型有可能推迟昂贵的临床前研究,并对软骨修复策略进行比体内更细致的评估。
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引用次数: 0
Targeting caspase-8/c-FLIPL heterodimer in complex II promotes DL-mediated cell death. 靶向复合体 II 中的 caspase-8/c-FLIPL 异二聚体可促进 DL 介导的细胞死亡。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1471216
Laura K Hillert-Richter, Corinna König, Nikita V Ivanisenko, Dirk Reinhold, Inna N Lavrik

Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIPL heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIPL heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks.

死亡受体(DR)网络受控于死亡诱导信号复合体(DISC)和复合体 II 的组装。针对 caspase-8/c-FLIPL 异源二聚体开发了小分子 FLIPins(FLIP 相互作用体)家族。研究表明,在 CD95L 和 TRAIL 等死亡配体(DLs)的刺激下,FLIPin 化合物可促进细胞凋亡和 DISC 上的 caspase-8 激活。为了进一步研究FLIPin化合物在DL介导的细胞死亡反应中的作用,我们分析了它们与DLs和SMAC模拟物联合处理的效果。研究发现,在急性髓性白血病(AML)、结肠癌和胰腺癌细胞中,FLIPin能增强DL和SMAC模拟物诱导的细胞活力丧失和细胞死亡。FLIPins通过增加复合体II的形成,增强了DL/BV6诱导的细胞凋亡和DL/BV6/zVAD-fm诱导的细胞坏死。我们的研究结果表明,靶向caspase-8/c-FLIPL异源二聚体在增强DL/SMAC模拟物共同刺激诱导的细胞死亡中发挥着重要作用,并为靶向DR网络开辟了新的治疗策略。
{"title":"Targeting caspase-8/c-FLIP<sub>L</sub> heterodimer in complex II promotes DL-mediated cell death.","authors":"Laura K Hillert-Richter, Corinna König, Nikita V Ivanisenko, Dirk Reinhold, Inna N Lavrik","doi":"10.3389/fcell.2024.1471216","DOIUrl":"https://doi.org/10.3389/fcell.2024.1471216","url":null,"abstract":"<p><p>Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIP<sub>L</sub> heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIP<sub>L</sub> heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1471216"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The potential of diallyl trisulfide for cancer prevention and treatment, with mechanism insights. 二烯丙基三硫在预防和治疗癌症方面的潜力,以及对其机理的见解。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1450836
Ling Lu, Zihan Gao, Jiajia Song, Longtao Jin, Zhaofeng Liang

Cancer has become an important public health problem worldwide, and there is currently a lack of effective treatment and prevention strategies. Natural plant active ingredients have been proven to be a safe and highly promising method for preventing and treating cancer. It has been found that diallyl trisulfide have anticancer effects in multiple types of cancer via inhibiting cancer proliferation, enhancing chemotherapy sensitivity, inducing apoptosis/autophagy, suppressing invasion/migration, regulating microenvironment. With the deepening of research on new strategies for cancer prevention and treatment, the role of diallyl trisulfides in cancers occurrence, prognosis, and drug resistance is also receiving increasing attention. In order to better understand the relationship between diallyl trisulfides and various cancer, as well as the role and mechanism of diallyl trisulfides in cancer prevention and treatment, we briefly summarized the role and function of diallyl trisulfide in cancers.

癌症已成为全球重要的公共卫生问题,目前缺乏有效的治疗和预防策略。天然植物活性成分已被证明是一种安全且极具前景的癌症预防和治疗方法。研究发现,二烯丙基三硫化物通过抑制癌细胞增殖、提高化疗敏感性、诱导细胞凋亡/自噬、抑制侵袭/迁移、调节微环境等途径,对多种癌症具有抗癌作用。随着癌症预防和治疗新策略研究的深入,二烯丙基三硫化物在癌症发生、预后和耐药性中的作用也日益受到关注。为了更好地了解二烯丙基三硫化物与各种癌症的关系,以及二烯丙基三硫化物在癌症防治中的作用和机制,我们简要总结了二烯丙基三硫化物在癌症中的作用和功能。
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引用次数: 0
Editorial: Breakthroughs in tumor stem cell research. 社论:肿瘤干细胞研究的突破。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-27 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1492867
Ming-Chuan Hsu
{"title":"Editorial: Breakthroughs in tumor stem cell research.","authors":"Ming-Chuan Hsu","doi":"10.3389/fcell.2024.1492867","DOIUrl":"https://doi.org/10.3389/fcell.2024.1492867","url":null,"abstract":"","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1492867"},"PeriodicalIF":4.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Editorial: Lipid alterations in cancer development, resistance and recurrence. 社论:癌症发展、抗药性和复发中的脂质改变。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-27 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1493626
F Pagliari, S Di Franco, L Tirinato
{"title":"Editorial: Lipid alterations in cancer development, resistance and recurrence.","authors":"F Pagliari, S Di Franco, L Tirinato","doi":"10.3389/fcell.2024.1493626","DOIUrl":"https://doi.org/10.3389/fcell.2024.1493626","url":null,"abstract":"","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"12 ","pages":"1493626"},"PeriodicalIF":4.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Regulation of p53 by the mitotic surveillance/stopwatch pathway: implications in neurodevelopment and cancer. 有丝分裂监控/停表途径对 p53 的调控:对神经发育和癌症的影响。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-27 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1451274
Travis H Stracker

The transcription factor p53 (encoded by TP53) plays diverse roles in human development and disease. While best known for its role in tumor suppression, p53 signaling also influences mammalian development by triggering cell fate decisions in response to a wide variety of stresses. After over 4 decades of study, a new pathway that triggers p53 activation in response to mitotic delays was recently identified. Termed the mitotic surveillance or mitotic stopwatch pathway, the USP28 and 53BP1 proteins activate p53 in response to delayed mitotic progression to control cell fate and promote genomic stability. In this Minireview, I discuss its identification, potential roles in neurodevelopmental disorders and cancer, as well as explore outstanding questions about its function, regulation and potential use as a biomarker for anti-mitotic therapies.

转录因子 p53(由 TP53 编码)在人类发育和疾病中发挥着多种作用。虽然 p53 信号在抑制肿瘤方面的作用最为人熟知,但它还能在各种压力下触发细胞命运决定,从而影响哺乳动物的发育。经过 40 多年的研究,最近发现了一种新的途径,它能触发 p53 激活以应对有丝分裂延迟。USP28 和 53BP1 蛋白被称为有丝分裂监控或有丝分裂秒表途径,它们会激活 p53 以应对有丝分裂进程的延迟,从而控制细胞命运并促进基因组稳定性。在本微型访谈中,我将讨论它的鉴定、在神经发育障碍和癌症中的潜在作用,并探讨有关它的功能、调控和作为抗有丝分裂疗法生物标记物的潜在用途等悬而未决的问题。
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引用次数: 0
Cytokinetic contractile ring structural progression in an early embryo: positioning of scaffolding proteins, recruitment of α-actinin, and effects of myosin II inhibition. 早期胚胎中细胞运动收缩环结构的发展:支架蛋白的定位、α-肌动蛋白的招募以及肌球蛋白 II 抑制的影响。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-09-27 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1483345
John H Henson, Gabriela Reyes, Nina T Lo, Karina Herrera, Quenelle W McKim, Hannah Y Herzon, Maritriny Galvez-Ceron, Alexandra E Hershey, Rachael S Kim, Charles B Shuster

Our knowledge of the assembly and dynamics of the cytokinetic contractile ring (CR) in animal cells remains incomplete. We have previously used super-resolution light microscopy and platinum replica electron microscopy to elucidate the ultrastructural organization of the CR in first division sea urchin embryos. To date, our studies indicate that the CR initiates as an equatorial band of clusters containing myosin II, actin, septin and anillin, which then congress over time into patches which coalesce into a linear array characteristic of mature CRs. In the present study, we applied super-resolution interferometric photoactivated localization microscopy to confirm the existence of septin filament-like structures in the developing CR, demonstrate the close associations between septin2, anillin, and myosin II in the CR, as well as to show that septin2 appears consistently submembranous, whereas anillin is more widely distributed in the early CR. We also provide evidence that the major actin cross-linking protein α-actinin only associates with the linearized, late-stage CR and not with the early CR clusters, providing further support to the idea that α-actinin associates with actomyosin structures under tension and can serve as a counterbalance. In addition, we show that inhibition of actomyosin contraction does not stop the assembly of the early CR clusters but does arrest the progression of these structures to the aligned arrays required for functional cytokinesis. Taken together our results reinforce and extend our model for a cluster to patch to linear structural progression of the CR in sea urchin embryos and highlight the evolutionary relationships with cytokinesis in fission yeast.

我们对动物细胞中细胞运动收缩环(CR)的组装和动力学的了解仍然不全面。我们以前曾使用超分辨率光学显微镜和铂复制电子显微镜来阐明第一次分裂海胆胚胎中 CR 的超微结构组织。迄今为止,我们的研究表明,CR 最初是由包含肌球蛋白 II、肌动蛋白、 septin 和 anillin 的簇组成的赤道带,然后随着时间的推移逐渐形成斑块,最后凝聚成成熟 CR 所特有的线性阵列。在本研究中,我们应用超分辨率干涉光电激活定位显微镜证实了发育中的CR中存在septin丝状结构,证明了CR中septin2、anillin和肌球蛋白II之间的密切联系,并表明septin2始终处于膜下,而anillin在早期CR中分布更广。我们还提供证据表明,主要肌动蛋白交联蛋白α-actinin只与线性化的晚期CR结合,而不与早期CR簇结合,这进一步支持了α-actinin在张力作用下与肌动蛋白结构结合并起到平衡作用的观点。此外,我们还发现,抑制肌动蛋白收缩并不能阻止早期 CR 簇的组装,但却能阻止这些结构向功能性细胞运动所需的排列阵列发展。总之,我们的研究结果加强并扩展了我们的模型,即海胆胚胎中 CR 的集群到线性结构进展的修补,并突出了与裂殖酵母细胞分裂的进化关系。
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引用次数: 0
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