{"title":"Rapamycin Abrogates Aggregation of Human α-Synuclein Expressed in Fission Yeast via an Autophagy-Independent Mechanism","authors":"Yoshitaka Sugimoto, Teruaki Takasaki, Ryuga Yamada, Ryo Kurosaki, Tomonari Yamane, Reiko Sugiura","doi":"10.1111/gtc.13185","DOIUrl":"10.1111/gtc.13185","url":null,"abstract":"<div>\u0000 \u0000 <p>Aggregation of alpha-synuclein (α-Syn) is implicated in the pathogenesis of several neurodegenerative disorders, such as Parkinson's disease and Dementia with Lewy bodies, collectively termed synucleinopathies. Thus, tremendous efforts are being made to develop strategies to prevent or inhibit α-Syn aggregation. Here, we genetically engineered fission yeast to express human α-Syn C-terminally fused to green fluorescent protein (GFP) at low and high levels. α-Syn was localized at the cell tips and septa at low-level expression. At high-level expression, α-Syn was observed to form cytoplasmic aggregates. Notably, rapamycin, a natural product that allosterically inhibits the mammalian target of rapamycin (mTOR) by forming a complex with FKBP12, and Torin1, a synthetic mTOR inhibitor that blocks ATP binding to mTOR, markedly reduced the number of cells harboring α-Syn aggregates. These mTOR inhibitors abrogate α-Syn aggregation without affecting α-Syn expression levels. Rapamycin, but not Torin1, failed to reduce α-Syn aggregation in the deletion cells of <i>fkh1</i><sup>+</sup>, encoding FKBP12, indicating the requirement of FKBP12 for rapamycin-mediated inhibition of α-Syn aggregation. Importantly, the effect of rapamycin was also observed in the cells lacking <i>atg1</i><sup>+</sup>, a key regulator of autophagy. Collectively, rapamycin abrogates human α-Syn aggregation expressed in fission yeast via an autophagy-independent mechanism mediated by FKBP12.</p>\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Defects in the H3t Gene Cause an Increase in Leydig Cells With Impaired Spermatogenesis in Mice","authors":"Qianmei Wu, Miho Ito, Takeru Fujii, Kaori Tanaka, Kohta Nakatani, Yoshihiro Izumi, Takeshi Bamba, Takashi Baba, Kazumitsu Maehara, Kosuke Tomimatsu, Tatsuya Takemoto, Yasuyuki Ohkawa, Akihito Harada","doi":"10.1111/gtc.13182","DOIUrl":"10.1111/gtc.13182","url":null,"abstract":"<p>Abnormalities in spermatogenesis, a fundamental component of male reproductive function, can cause male infertility. Somatic cells constituting the testis microenvironment are essential for controlling normal spermatogenesis. Although testicular somatic cells are thought to sense and respond to germ cells to ensure proper spermatogenesis, the details of this signaling mechanism are unknown. Here, we investigated somatic cell dynamics in testicular tissue lacking spermatogenesis using the mice with deletion of the testis-specific histone H3 variant gene <i>H3t</i>. Testicular tissue sections of H3t<sup>Δ/Δ</sup> mice exhibited an increased interstitial area compared with those of wild-type mice, which was primarily attributed to an increase in Leydig cell numbers. Furthermore, this increase in Leydig cells led to increased testosterone synthesis, which occurred alongside cellular senescence-associated β-galactosidase activity. These findings suggest that Leydig cells monitor the progress of spermatogenesis and possess a mechanism to promote functional germ cell formation.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes to CellsPub Date : 2024-12-03DOI: 10.1111/gtc.13183
Kazuma Ohshima, Satoru Torii, Shigeomi Shimizu
{"title":"Presence of Gut Microbiota Worsens D-Galactosamine and Lipopolysaccharide-Induced Hepatic Injury in Mice","authors":"Kazuma Ohshima, Satoru Torii, Shigeomi Shimizu","doi":"10.1111/gtc.13183","DOIUrl":"10.1111/gtc.13183","url":null,"abstract":"<div>\u0000 \u0000 <p>Acute liver failure is a serious, life-threatening disease. Although the gut microbiota has been considered to play a role in liver failure, the extent to which it is involved in the pathogenesis of this disease has not been fully elucidated to date. Therefore, we here analyzed the importance of the presence of intestinal microbiota in the pathogenesis of acute liver injury, using D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated mice, which is a widely used experimental model of acute liver injury. First, administration of the antibiotic polymyxin B markedly alleviated liver injury. Liver injury was also reduced in germ-free mice, leading to the conclusion that the presence of intestinal microbiota aggravates D-GalN/LPS-induced liver injury. The amount of bacteria and LPS transferred from the gut to the blood was not increased by D-GalN/LPS, suggesting that the worsening of liver injury was not simply owing to the entry of bacteria into the circulation. In conclusion, acute liver injury in polymyxin B-pretreated or germ-free mice was ameliorated by modulation of the gut microbiota. Modification of the gut microbiota using polymyxin B may hence have the potential to alleviate acute liver injury in human patients.</p>\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Image Analysis Characterizes Phenotypic Variation in the Growth of Mushroom-Forming Fungus Schizophyllum commune","authors":"Hiromi Matsumae, Megumi Sudo, Tadashi Imanishi, Tsuyoshi Hosoya","doi":"10.1111/gtc.13181","DOIUrl":"10.1111/gtc.13181","url":null,"abstract":"<div>\u0000 \u0000 <p><i>Schizophyllum commune</i>, a common wood-decay mushroom known for its extremely high genetic variation and as a rare cause of human respiratory diseases, could be a promising model fungus contributing to both biology and medicine. To better understand its phenotypic variation, we developed an image analysis system that quantifies morphological and physiological traits of mycelial colonies in Petri dishes. This study evaluated growth of six wild and one clinical isolates of Japanese <i>S. commune</i>, subjected to different temperatures and glucose concentrations, including a condition mimicking the human respiratory environment. Our analysis revealed that combinations of two growth indices, area and whiteness, and profiling by clustering algorithms highlighted strain-specific responses. For example, the clinical isolate was the whitest under the respiratory-like condition. We also found that the growth rate was strongly determined by glucose concentration, while the effects of temperature on growth varied among the strains, suggesting that while glucose preference is common in this species, responses to temperature differ between strains. This system showed sufficient sensitivity to detect variation in mycelial growth. Our study provides a key to unraveling morphological and physiological traits behind the high polymorphisms in <i>S. commune</i>, including the ability to colonize the human respiratory tract.</p>\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Generation of Monosomy 21q Human iPS Cells by CRISPR/Cas9-Mediated Interstitial Megabase Deletion","authors":"Masaya Egawa, Narumi Uno, Rina Komazaki, Yusuke Ohkame, Kyotaro Yamazaki, Chihiro Yoshimatsu, Yuki Ishizu, Yusaku Okano, Hitomaru Miyamoto, Mitsuhiko Osaki, Teruhiko Suzuki, Kazuyoshi Hosomichi, Yasunori Aizawa, Yasuhiro Kazuki, Kazuma Tomizuka","doi":"10.1111/gtc.13184","DOIUrl":"10.1111/gtc.13184","url":null,"abstract":"<p>Missing an entire chromosome or chromosome arm in normal diploid cells has a deleterious impact on cell viability, which may contribute to the development of specific birth defects. Nevertheless, the effects of chromosome loss in human cells have remained unexplored due to the lack of suitable model systems. Here, we developed an efficient, selection-free approach to generate partial monosomy in human induced pluripotent stem cells (iPSCs). The introduction of Cas9 proteins and a pair of gRNAs induces over megabase-sized interstitial chromosomal deletions. Using human chromosome 21 (HSA21) as a model, partial monosomy 21q (PM21q) iPSC lines with deletions ranging from 4.5 to 27.9 Mb were isolated. A 33.6 Mb deletion, encompassing all protein-coding genes on 21q, was also achieved, establishing the first 21q monosomy human iPSC line. Transcriptome and proteome analyses revealed that the abundances of mRNA and protein encoded by the majority of genes in the monosomic regions are half of the diploid expression level, indicating an absence of dosage compensation. The ability to generate customized partial monosomy cell lines on an isogenic, karyotypically normal background should facilitate the gain of novel insights into the impact of chromosome loss on cellular fitness.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chromosomal rearrangements associated with SMC5/6 deficiency in DNA replication","authors":"Yoshiharu Kusano, Yasuha Kinugasa, Satoshi Tashiro, Toru Hirota","doi":"10.1111/gtc.13180","DOIUrl":"10.1111/gtc.13180","url":null,"abstract":"<p>Completion of DNA replication before chromosome segregation is essential for the stable maintenance of the genome. Under replication stress, DNA synthesis may persist beyond S phase, especially in genomic regions that are difficult to proceed with the replication processes. Incomplete replication in mitosis emerges as non-disjoined segment in mitotic chromosomes leading to anaphase bridges. The resulting chromosome rearrangements are not well characterized, however. Here, we report that incomplete replication due to SMC5/6 deficiency impairs sister chromatid disjunction at difficult-to-replicate regions, including common fragile sites. These non-disjoined regions manifest as cytologically defined symmetric gaps, causing anaphase bridges. These bridges break at the gaps, leading to telomere loss, micronucleation, and fragmentation. Subsequently, fusions between telomere-deficient chromosomes generate complex chromosomal rearrangements, including dicentric chromosomes, suggesting the occurrence of breakage-fusion-bridge cycle. Additionally, chromosomes in micronuclei were pulverized, indicative of chromothripsis. Our findings suggest that incomplete replication facilitates complex chromosomal rearrangements, which may contribute to genomic instability in human cancers.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1251-1263"},"PeriodicalIF":1.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes to CellsPub Date : 2024-11-05DOI: 10.1111/gtc.13178
Gaurav Das, Olfat A. Malak, Khushboo Sharma, Abdalla G. Alia, Swetha Gopalakrishnan, Reshma V. Menon, Hayato M. Yamanouchi, Akinao Nose, Hokto Kazama, Adrian W. Moore, Takashi Suzuki
{"title":"The fly brain lands in Tokyo: A report on the 3rd Asia Pacific Drosophila Neurobiology Conference","authors":"Gaurav Das, Olfat A. Malak, Khushboo Sharma, Abdalla G. Alia, Swetha Gopalakrishnan, Reshma V. Menon, Hayato M. Yamanouchi, Akinao Nose, Hokto Kazama, Adrian W. Moore, Takashi Suzuki","doi":"10.1111/gtc.13178","DOIUrl":"10.1111/gtc.13178","url":null,"abstract":"<p>The third Asia Pacific <i>Drosophila</i> Neurobiology Conference (APDNC3) was held in the Wako Campus of RIKEN in Tokyo, Japan, from February 27th to March 1st, 2024. While APDNC2 was held in Taiwan in 2019, the global coronavirus pandemic enforced a long hiatus. Hence, APDNC3 was a much-anticipated meeting that attracted ~218 scientists from 18 different countries and regions, 154 from outside Japan. The meeting was divided into 13 scientific, 2 poster, and 3 career development sessions. Two plenary talks were delivered by Professor Daisuke Yamamoto, from NICT and Professor Claude Desplan from NYU. Thirty-seven other speakers were invited to give lectures. Eighty-six poster presenters were selected from submitted abstracts. Talks and posters described how neuronal circuits underlying specific behaviors were identified and how they developed. The presented work also demonstrated circuit-specific cellular and molecular mechanisms in health and disease. It was clear that technological advances, like molecular genetic tools for identifying, manipulating, and imaging individual neurons and the great granularity of the fly brain connectome, were significantly augmenting research. Overall, the meeting highlighted the remarkable biological insights that fly neurobiologists continue to provide.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1111-1117"},"PeriodicalIF":1.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Immunotherapy-induced reprogramming of cancer-associated fibroblasts can promote tumor progression","authors":"Tomoya Yamashita, Haruki Horiguchi, Tsuyoshi Kadomatsu, Michio Sato, Toshiro Moroishi, Yuichi Oike","doi":"10.1111/gtc.13177","DOIUrl":"10.1111/gtc.13177","url":null,"abstract":"<p>Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, ICI initiation can also cause an unexpectedly rapid acceleration of cancer progression in some patients. Here, we used a murine syngeneic melanoma model to conduct mechanistic analysis of cancer-associated fibroblast (CAF) function in cancer progression in the context of immunotherapy. We found that after ICI treatment CAFs acquire inflammatory properties, which can promote tumor progression. Mechanistically, we show that T-cell-derived interferon-γ (IFN-γ) stimulates production of tumor necrosis factor-α (TNF-α) by macrophages, facilitating CAF conversion to inflammatory CAFs. Our findings suggest that CAF/immune cell crosstalk plays an essential role in ICI-associated tumor progression.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1275-1283"},"PeriodicalIF":1.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mrc1Claspin is essential for heterochromatin maintenance in Schizosaccharomyces pombe","authors":"Kei Kawakami, Yukari Ueno, Nao Hayama, Katsunori Tanaka","doi":"10.1111/gtc.13175","DOIUrl":"10.1111/gtc.13175","url":null,"abstract":"<p>In eukaryotes, maintenance of heterochromatin structure that represses gene expression during cell proliferation is essential for guaranteeing cell identity. However, how heterochromatin is maintained and transmitted to the daughter cells remains elusive. In this study, we constructed a reporter system to study the maintenance of heterochromatin in the subtelomeric region of the fission yeast, <i>Schizosaccharomyces pombe</i>. We demonstrated that once subtelomeric heterochromatin was established, it tended to be maintained as a metastable structure through cell proliferation. Using this system, we screened an <i>S. pombe</i> genome-wide gene deletion library for subtelomeric heterochromatin maintenance factors and identified 57 genes related to various cellular processes, in addition to well-characterized heterochromatin factors. We focused on Mrc1<sup>Claspin</sup>, a mediator of DNA replication checkpoint. We found that Mrc1 maintains heterochromatin structure not only at the subtelomeres but also at the pericentromeres and mating-type regions. Furthermore, we showed that Mrc1 is required for the localization of Snf2/Hdac-containing Repressor Complex (SHREC) and the maintenance of hypoacetylation state of histone H3K14. This study complements the recent discoveries that Mrc1 functions as a histone H3-H4 chaperone in heterochromatin maintenance.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1207-1224"},"PeriodicalIF":1.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pathogen challenge in Arabidopsis cotyledons induces enhanced disease resistance at newly formed rosette leaves via sustained upregulation of WRKY70","authors":"Kanoknipa Sukaoun, Tokuji Tsuchiya, Hiroshi Uchiyama","doi":"10.1111/gtc.13179","DOIUrl":"10.1111/gtc.13179","url":null,"abstract":"<p>Pathogenic microorganisms often target seedlings shortly after germination. If plants exhibit resistance or resilience to pathogens, those exposed to pathogen challenge may grow further and form new unchallenged leaves. The purpose of this study was to examine disease resistance in the newly formed leaves of plants subjected to pathogen challenge. We used <i>Arabidopsis thaliana</i> and the oomycete pathogen <i>Hyaloperonospora arabidopsidis</i> (<i>Hpa</i>) as the model pathosystem. We found that Arabidopsis seedlings primarily challenged with the avirulent isolate <i>Hpa</i> exhibited enhanced disease resistance against the virulent isolate <i>Hpa</i> in newly formed rosette leaves (NFRLs). Our observations indicated that the transcript levels of the transcription factor gene <i>WRKY70</i>, which is essential for full resistance to the virulent isolate <i>Hpa</i>Noco2, were elevated and maintained at high levels in the NFRLs. In contrast, the transcript levels of the salicylic acid marker gene <i>PR1</i> and systemic acquired resistance-related genes did not exhibit sustained elevation. The maintenance of increased transcript levels of <i>WRKY70</i> operated independently of non-expressor of pathogenesis-related gene 1. These findings suggest that prolonged upregulation of <i>WRKY70</i> represents a defensive state synchronized with plant development to ensure survival against subsequent infections.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1236-1250"},"PeriodicalIF":1.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}