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Rapid human oogonia-like cell specification via transcription factor-directed differentiation.
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-23 DOI: 10.1038/s44319-025-00371-2
Merrick Pierson Smela, Christian C Kramme, Patrick R J Fortuna, Bennett Wolf, Shrey Goel, Jessica Adams, Carl Ma, Sergiy Velychko, Ursula Widocki, Venkata Srikar Kavirayuni, Tianlai Chen, Sophia Vincoff, Edward Dong, Richie E Kohman, Mutsumi Kobayashi, Toshi Shioda, George M Church, Pranam Chatterjee

The generation of germline cells from human induced pluripotent stem cells (hiPSCs) represents a milestone toward in vitro gametogenesis. Methods to recapitulate germline development beyond primordial germ cells in vitro have relied on long-term cell culture, such as 3-dimensional organoid co-culture for ~four months. Using a pipeline with highly parallelized screening, this study identifies combinations of TFs that directly and rapidly convert hiPSCs to induced oogonia-like cells (iOLCs). We demonstrate that co-expression of five TFs - namely, ZNF281, LHX8, SOHLH1, ZGLP1, and ANHX, induces high efficiency DDX4-positive iOLCs in only four days in a feeder-free monolayer culture condition. We also show improved production of human primordial germ cell-like cells (hPGCLCs) from hiPSCs by expression of DLX5, HHEX, and FIGLA. We characterize these TF-based iOLCs and hPGCLCs via gene and protein expression analyses and demonstrate their similarity to in vivo and in vitro-derived oogonia and primordial germ cells. Together, these results identify new regulatory factors that enhance human germ cell specification in vitro, and further establish unique computational and experimental tools for human in vitro oogenesis research.

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引用次数: 0
Natural variations of adolescent neurogenesis and anxiety predict the hierarchical status of adult inbred mice.
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-23 DOI: 10.1038/s44319-025-00367-y
Fabio Grieco, Atik Balla, Thomas Larrieu, Nicolas Toni

Hierarchy provides a survival advantage to social animals in challenging circumstances. In mice, social dominance is associated with trait anxiety which is regulated by adult hippocampal neurogenesis. Here, we test whether adolescent hippocampal neurogenesis may regulate social dominance behavior in adulthood. We observe that adolescent individuals with higher trait anxiety and lower levels of hippocampal neurogenesis prior to the formation of a new group become dominants, suggesting that baseline adolescent neurogenesis predicts hierarchical status. This phenotype persists beyond social hierarchy stabilization. Experimentally reducing neurogenesis prior to the stabilization of social hierarchy in group-housed adolescent males increases the probability of mice to become dominant and increases anxiety. Finally, when innate dominance is assessed in socially isolated and anxiety-matched animals, mice with impaired neurogenesis display a dominant status toward strangers. Together, these results indicate that adolescent neurogenesis predicts and regulates hierarchical and situational dominance behavior along with anxiety-related behavior. These results provide a framework to study the mechanisms underlying social hierarchy and the dysregulation of dominance behavior in psychiatric diseases related to anxiety.

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引用次数: 0
High CDC20 levels increase sensitivity of cancer cells to MPS1 inhibitors. 高CDC20水平会增加癌细胞对MPS1抑制剂的敏感性。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-21 DOI: 10.1038/s44319-024-00363-8
Siqi Zheng, Linoy Raz, Lin Zhou, Yael Cohen-Sharir, Ruifang Tian, Marica Rosaria Ippolito, Sara Gianotti, Ron Saad, Rene Wardenaar, Mathilde Broekhuis, Maria Suarez Peredo Rodriguez, Soraya Wobben, Anouk van den Brink, Petra Bakker, Stefano Santaguida, Floris Foijer, Uri Ben-David

Spindle assembly checkpoint (SAC) inhibitors are a recently developed class of drugs, which perturb chromosome segregation during cell division, induce chromosomal instability (CIN), and eventually lead to cell death. The molecular features that determine cellular sensitivity to these drugs are not fully understood. We recently reported that aneuploid cancer cells are preferentially sensitive to SAC inhibition. Here we report that sensitivity to SAC inhibition by MPS1 inhibitors is largely driven by the expression of CDC20, a main mitotic activator of the anaphase-promoting complex (APC/C), and that the effect of CDC20 is larger than that of the APC/C itself. Mechanistically, we discovered that CDC20 depletion prolongs metaphase duration, diminishes mitotic errors, and reduces sensitivity to SAC inhibition. We found that aneuploid cells express higher basal levels of CDC20, which shortens the duration of metaphase and leads to multiple mitotic errors, resulting in increased long-term sensitivity to the additional CIN induced by SAC inhibition. Our findings propose high CDC20 expression as a molecular feature associated with the sensitivity to SAC inhibition therapy and as a potential aneuploidy-induced cellular vulnerability.

纺锤体组装检查点(SAC)抑制剂是最近开发的一类药物,它在细胞分裂过程中扰乱染色体分离,诱导染色体不稳定(CIN),最终导致细胞死亡。决定细胞对这些药物敏感性的分子特征尚不完全清楚。我们最近报道了非整倍体癌细胞对SAC抑制优先敏感。在这里,我们报道了MPS1抑制剂对SAC抑制的敏感性在很大程度上是由CDC20的表达驱动的,CDC20是后期促进复合体(APC/C)的主要有丝分裂激活剂,并且CDC20的作用大于APC/C本身。在机制上,我们发现CDC20缺失延长了中期持续时间,减少了有丝分裂错误,降低了对SAC抑制的敏感性。我们发现非整倍体细胞表达更高的CDC20基础水平,这缩短了中期持续时间并导致多次有丝分裂错误,导致对SAC抑制诱导的额外CIN的长期敏感性增加。我们的研究结果表明,高CDC20表达是与SAC抑制治疗敏感性相关的分子特征,也是潜在的非整倍体诱导的细胞易感性。
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引用次数: 0
The controls that got out of control : How failed control experiments paved the way to transformative discoveries. 失控的控制:失败的控制实验如何为变革性的发现铺平道路。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-20 DOI: 10.1038/s44319-025-00369-w
André Schneider
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引用次数: 0
Male sex determination maintains proteostasis and extends lifespan of daf-18/PTEN deficient C. elegans. 雄性性别决定维持daf-18/PTEN缺陷秀丽隐杆线虫的蛋白质平衡并延长其寿命。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-16 DOI: 10.1038/s44319-025-00368-x
Zhi Qu, Lu Zhang, Xue Yin, Fangzhou Dai, Wei Huang, Yutong Zhang, Dongyang Ran, Shanqing Zheng

Although females typically have a survival advantage, those with PTEN functional abnormalities face a higher risk of developing tumors than males. However, the differences in how each sex responds to PTEN dysfunction have rarely been studied. We use Caenorhabditis elegans to investigate how male and hermaphrodite worms respond to dysfunction of the PTEN homolog daf-18. Our study reveals that male worms can counterbalance the negative effects of daf-18 deficiency, resulting in longer adult lifespan. The survival advantage depends on the loss of DAF-18 protein phosphatase activity, while its lipid phosphatase activity is dispensable. The deficiency in DAF-18 protein phosphatase activity leads to the failure of dephosphorylation of the endoplasmic reticulum membrane protein C18E9.2/SEC62, causing increased levels of unfolded and aggregated proteins in hermaphrodites. In contrast, males maintain proteostasis through a UNC-23/NEF-mediated protein ubiquitination and degradation process, providing them with a survival advantage. We find that sex determination is a key factor in regulating the differential expression of unc-23 between sexes in response to daf-18 loss. These findings highlight the unique role of the male sex determination pathway in regulating protein degradation.

尽管女性通常具有生存优势,但PTEN功能异常的女性患肿瘤的风险高于男性。然而,两性对PTEN功能障碍的反应差异很少被研究。我们使用秀丽隐杆线虫来研究雄性和雌雄同体线虫对PTEN同源物daf-18功能障碍的反应。我们的研究表明,雄性蠕虫可以抵消daf-18缺乏的负面影响,从而延长成虫的寿命。生存优势取决于DAF-18蛋白磷酸酶活性的丧失,而其脂质磷酸酶活性则可有可无。DAF-18蛋白磷酸酶活性缺乏导致内质网膜蛋白C18E9.2/SEC62去磷酸化失败,导致雌雄同体中未折叠和聚集蛋白水平升高。相比之下,雄性通过UNC-23/ nef介导的蛋白质泛素化和降解过程维持蛋白质稳态,为它们提供了生存优势。我们发现性别决定是调节性别间unc-23表达差异以应对daf-18缺失的关键因素。这些发现强调了男性性别决定途径在调节蛋白质降解中的独特作用。
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引用次数: 0
Author Correction: PP4 is a γH2AX phosphatase required for recovery from the DNA damage checkpoint. 作者更正:PP4 是一种从 DNA 损伤检查点恢复所需的γH2AX 磷酸酶。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-14 DOI: 10.1038/s44319-024-00338-9
Shinichiro Nakada, Ginny I Chen, Anne-Claude Gingras, Daniel Durocher
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引用次数: 0
CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery. CRISPR-Enabled Autonomous Transposable Element (CREATE)用于基于rna的基因编辑和传递。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.1038/s44319-024-00364-7
Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts

To address a wide range of genetic diseases, genome editing tools that can achieve targeted delivery of large genes without causing double-strand breaks (DSBs) or requiring DNA templates are necessary. Here, we introduce CRISPR-Enabled Autonomous Transposable Element (CREATE), a genome editing system that combines the programmability and precision of CRISPR/Cas9 with the RNA-mediated gene insertion capabilities of the human LINE-1 (L1) element. CREATE employs a modified L1 mRNA to carry a payload gene, and a Cas9 nickase to facilitate targeted editing by L1-mediated reverse transcription and integration without relying on DSBs or DNA templates. Using this system, we demonstrate programmable insertion of a 1.1 kb gene expression cassette into specific genomic loci of human cell lines and primary T cells. Mechanistic studies reveal that CREATE editing is highly specific with no observed off-target events. Together, these findings establish CREATE as a programmable, RNA-based gene delivery technology with broad therapeutic potential.

为了解决广泛的遗传疾病,基因组编辑工具是必要的,它可以在不引起双链断裂(dsb)或不需要DNA模板的情况下实现大基因的靶向递送。在这里,我们介绍了CRISPR- enabled Autonomous Transposable Element (CREATE),这是一种基因组编辑系统,将CRISPR/Cas9的可编程性和精确性与人类LINE-1 (L1)元件的rna介导的基因插入能力相结合。CREATE使用修饰的L1 mRNA携带有效载荷基因和Cas9缺口酶,以促进L1介导的逆转录和整合的靶向编辑,而不依赖于dsb或DNA模板。使用该系统,我们演示了将1.1 kb的基因表达盒可编程插入到人类细胞系和原代T细胞的特定基因组位点中。机制研究表明,CREATE编辑是高度特异性的,没有观察到脱靶事件。总之,这些发现表明CREATE是一种可编程的、基于rna的基因传递技术,具有广泛的治疗潜力。
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引用次数: 0
Acidic pH can attenuate immune killing through inactivation of perforin. 酸性pH可以通过穿孔素失活来减弱免疫杀伤。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.1038/s44319-024-00365-6
Adrian W Hodel, Jesse A Rudd-Schmidt, Tahereh Noori, Christopher J Lupton, Veronica C T Cheuk, Joseph A Trapani, Bart W Hoogenboom, Ilia Voskoboinik

Cytotoxic lymphocytes are crucial to our immune system, primarily eliminating virus-infected or cancerous cells via perforin/granzyme killing. Perforin forms transmembrane pores in the plasma membrane, allowing granzymes to enter the target cell cytosol and trigger apoptosis. The prowess of cytotoxic lymphocytes to efficiently eradicate target cells has been widely harnessed in immunotherapies against haematological cancers. Despite efforts to achieve a similar outcome against solid tumours, the immunosuppressive and acidic tumour microenvironment poses a persistent obstacle. Using different types of effector cells, including therapeutically relevant anti-CD19 CAR T cells, we demonstrate that the acidic pH typically found in solid tumours hinders the efficacy of immune therapies by impeding perforin pore formation within the immunological synapse. A nanometre-scale study of purified recombinant perforin undergoing oligomerization reveals that pore formation is inhibited specifically by preventing the formation of a transmembrane β-barrel. The absence of perforin pore formation directly prevents target cell death. This finding uncovers a novel layer of immune effector inhibition that must be considered in the development of effective immunotherapies for solid tumours.

细胞毒性淋巴细胞对我们的免疫系统至关重要,主要通过穿孔素/颗粒酶杀死病毒感染的细胞或癌细胞。穿孔素在质膜上形成跨膜孔,允许颗粒酶进入靶细胞的细胞质并引发细胞凋亡。细胞毒性淋巴细胞有效根除靶细胞的能力已被广泛应用于血液学癌症的免疫治疗中。尽管努力在实体瘤中取得类似的结果,但免疫抑制和酸性肿瘤微环境构成了一个持续的障碍。使用不同类型的效应细胞,包括治疗相关的抗cd19 CAR - T细胞,我们证明了在实体肿瘤中通常发现的酸性pH值通过阻碍免疫突触内穿孔孔的形成而阻碍免疫治疗的疗效。一项纳米尺度的纯化重组穿孔蛋白寡聚化研究表明,通过阻止跨膜β-桶的形成,孔的形成被特异性地抑制。穿孔孔形成的缺失直接阻止了靶细胞的死亡。这一发现揭示了一种新的免疫效应抑制层,在开发有效的实体瘤免疫疗法时必须考虑到这一点。
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引用次数: 0
OTUD6B regulates KIFC1-dependent centrosome clustering and breast cancer cell survival. OTUD6B调节kifc1依赖性中心体聚集和乳腺癌细胞存活。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.1038/s44319-024-00361-w
Valeria E Marotta, Dorota Sabat-Pośpiech, Andrew B Fielding, Amy H Ponsford, Amanda Thomaz, Francesca Querques, Mark R Morgan, Ian A Prior, Judy M Coulson

Cancer cells often display centrosome amplification, requiring the kinesin KIFC1/HSET for centrosome clustering to prevent multipolar spindles and cell death. In parallel siRNA screens of deubiquitinase enzymes, we identify OTUD6B as a positive regulator of KIFC1 expression that is required for centrosome clustering in triple-negative breast cancer (TNBC) cells. OTUD6B can localise to centrosomes and the mitotic spindle and interacts with KIFC1. In OTUD6B-deficient cells, we see increased KIFC1 polyubiquitination and premature KIFC1 degradation during mitosis. Depletion of OTUD6B increases multipolar spindles without inducing centrosome amplification. Phenotypic rescue is dependent on OTUD6B catalytic activity and evident upon KIFC1 overexpression. OTUD6B is commonly overexpressed in breast cancer, correlating with KIFC1 protein expression and worse patient survival. TNBC cells with centrosome amplification, but not normal breast epithelial cells, depend on OTUD6B to proliferate. Indeed CRISPR-Cas9 editing results in only OTUD6B-/+ TNBC cells which fail to divide and die. As a deubiquitinase that supports KIFC1 expression, allowing pseudo-bipolar cell division and survival of cancer cells with centrosome amplification, OTUD6B has potential as a novel target for cancer-specific therapies.

癌细胞经常表现出中心体扩增,需要激酶KIFC1/HSET进行中心体聚集,以防止多极纺锤体和细胞死亡。在去泛素酶的平行siRNA筛选中,我们发现OTUD6B是三阴性乳腺癌(TNBC)细胞中心体聚集所必需的KIFC1表达的正调节因子。OTUD6B可以定位于中心体和有丝分裂纺锤体,并与KIFC1相互作用。在otud6b缺陷细胞中,我们看到有丝分裂期间KIFC1多泛素化增加和KIFC1过早降解。OTUD6B的缺失会增加多极纺锤体,但不会引起中心体扩增。表型拯救依赖于OTUD6B的催化活性,并在KIFC1过表达时表现明显。OTUD6B在乳腺癌中普遍过表达,与KIFC1蛋白表达和患者生存率降低相关。中心体扩增的TNBC细胞,而不是正常的乳腺上皮细胞,依靠OTUD6B来增殖。事实上,CRISPR-Cas9编辑只会导致OTUD6B-/+ TNBC细胞无法分裂并死亡。OTUD6B作为一种支持KIFC1表达的去泛素酶,允许假双极细胞分裂和中心体扩增的癌细胞存活,有潜力成为癌症特异性治疗的新靶点。
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引用次数: 0
Addendum: The history of GM crops in Italy. 附录:意大利转基因作物的历史。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.1038/s44319-024-00359-4
Roberto Defez, Maria Chiara Errigo, Giulia Formici, Lucia Scaffardi, Eleonora Sirsi, Fabio Fornara, Vittoria Brambilla
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引用次数: 0
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