Disease Models & Mechanisms最新文献_第2页

Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2. 通过诱导性敲除 nf2 生成斑马鱼神经纤维瘤病模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-17 DOI: 10.1242/dmm.050862

Ayyappa Raja Desingu Rajan, Yuanyun Huang, Jan Stundl, Katelyn Chu, Anushka Irodi, Zihan Yang, Brian E Applegate, Marianne E Bronner

{"title":"Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2.","authors":"Ayyappa Raja Desingu Rajan, Yuanyun Huang, Jan Stundl, Katelyn Chu, Anushka Irodi, Zihan Yang, Brian E Applegate, Marianne E Bronner","doi":"10.1242/dmm.050862","DOIUrl":"https://doi.org/10.1242/dmm.050862","url":null,"abstract":"Neurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout of nf2a/b, the zebrafish homolog of human NF2. Analysis of nf2a and nf2b expression reveals ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displays lower expression levels. Induction of nf2a/b knockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggers the development of a spectrum of tumors, including vestibular Schwannomas, spinal Schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimised methods to image hepatic lipid droplets in zebrafish larvae. 斑马鱼幼体肝脏脂滴成像的优化方法。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-07 DOI: 10.1242/dmm.050786

Nouf Khan, Talhah M Salmi, Anthony P Karamalakis, Anjana Ramdas Nair, Kirsten C Sadler, Andrew G Cox

{"title":"Optimised methods to image hepatic lipid droplets in zebrafish larvae.","authors":"Nouf Khan, Talhah M Salmi, Anthony P Karamalakis, Anjana Ramdas Nair, Kirsten C Sadler, Andrew G Cox","doi":"10.1242/dmm.050786","DOIUrl":"https://doi.org/10.1242/dmm.050786","url":null,"abstract":"The optical transparency of zebrafish larvae enables visualization of subcellular structures in intact organs, and these vertebrates are widely used to study lipid biology and liver disease. Lipid droplet (LD) presence is a prevalent feature of healthy cells but under conditions such as nutrient excess, toxicant exposure or metabolic imbalance, LD accumulation in hepatocytes can be a harbinger of more severe forms of liver disease. We undertook a comprehensive analysis of approaches useful to investigate LD distribution and dynamics in physiological and pathological conditions in the liver of zebrafish larvae. This comparative analysis of the lipid dyes oil red O (ORO), Nile Red (NR), LipidTox and LipidSpot as well as transgenic LD reporters that rely on EGFP fusions of the LD decorating protein perilipin 2 (PLIN2) demonstrate the strengths and limitations of each approach. These protocols are amenable to detection methods ranging from low resolution stereomicroscopy to confocal imaging, which enables measurements of hepatic LD size, number and dynamics at cellular resolution in live and fixed animals. This resource will benefit investigators studying LD biology in zebrafish disease models.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Welcoming new Editorial Advisory Board members. 欢迎新的编辑顾问委员会成员。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-28 DOI: 10.1242/dmm.052155

Dina Mikimoto, Kirsty Hooper

引用次数: 0

Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy. 在杜氏肌营养不良症 mdx 小鼠模型中，β 肾上腺素能应激诱导损伤对心脏功能的影响。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-09 DOI: 10.1242/dmm.050852

Conner C Earl, Areli J Javier, Alyssa M Richards, Larry W Markham, Craig J Goergen, Steven S Welc

{"title":"Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy.","authors":"Conner C Earl, Areli J Javier, Alyssa M Richards, Larry W Markham, Craig J Goergen, Steven S Welc","doi":"10.1242/dmm.050852","DOIUrl":"10.1242/dmm.050852","url":null,"abstract":"Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD); however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to stimulate injury and enhance cardiac pathology in the mdx model, many methods lead to high mortality with variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. mdx and wild-type mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathological assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes and diminished cardiac reserve in mdx compared to wild-type mice. Our findings highlight the utility of challenging mdx mice with low-dose isoproterenol as a valuable model for exploring therapies targeting DMD-associated cardiac pathologies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy. 肝部分切除术后斑马鱼肝细胞增殖的性别差异受性激素受体和 S100A1-YAP 信号级联的调控。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-30 DOI: 10.1242/dmm.050900

Mingkai Zhu, Yan Li, Qiaosen Shen, Zhiyuan Gong, Dong Liu

{"title":"Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy.","authors":"Mingkai Zhu, Yan Li, Qiaosen Shen, Zhiyuan Gong, Dong Liu","doi":"10.1242/dmm.050900","DOIUrl":"10.1242/dmm.050900","url":null,"abstract":"Partial hepatectomy (PH) is commonly used to treat patients with hepatocellular carcinoma. The recovery of patients from PH depends on the initiation of liver regeneration, a process that mainly relies on liver cell proliferation. As sex affects the human liver regeneration progress, we investigated sex disparity in PH-induced liver regeneration in adult zebrafish. We found that, after PH, males began liver regeneration earlier than females in terms of liver cell proliferation and liver mass recovery, and this was associated with earlier activation of Yap1 signaling in male than female livers. We also found that androgen receptors regulated the sex-biased liver regeneration in a Yap1-dependent manner and that activated estrogen receptors are responsible for the later onset of female hepatocyte proliferation. Furthermore, we identified that S100A1, a calcium-binding protein, regulates the sex disparity in liver regeneration, as heterozygous S100A1 knockout inhibited Yap1 activity in male livers and delayed hepatocyte proliferation in males following PH. Thus, multiple pathways and/or their interplays contribute to the sex disparity in liver regeneration, suggesting that sex-biased therapeutic strategies are required for patients who have received PH-based therapies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11556313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuromuscular junction dysfunction in Lafora disease. 拉弗拉病小鼠模型的神经肌肉接头功能障碍

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-14 DOI: 10.1242/dmm.050905

Monica Shukla, Deepti Chugh, Subramaniam Ganesh

{"title":"Neuromuscular junction dysfunction in Lafora disease.","authors":"Monica Shukla, Deepti Chugh, Subramaniam Ganesh","doi":"10.1242/dmm.050905","DOIUrl":"10.1242/dmm.050905","url":null,"abstract":"Lafora disease (LD), a fatal neurodegenerative disorder, is caused by mutations in the EPM2A gene encoding laforin phosphatase or NHLRC1 gene encoding malin ubiquitin ligase. LD symptoms include epileptic seizures, ataxia, dementia and cognitive decline. Studies on LD have primarily concentrated on the pathophysiology in the brain. A few studies have reported motor symptoms, muscle weakness and muscle atrophy. Intriguingly, skeletal muscles are known to accumulate Lafora polyglucosan bodies. Using laforin-deficient mice, an established model for LD, we demonstrate that LD pathology correlated with structural and functional impairments in the neuromuscular junction (NMJ). Specifically, we found impairment in NMJ transmission, which coincided with altered expression of NMJ-associated genes and reduced motor endplate area, fragmented junctions and loss of fully innervated junctions at the NMJ. We also observed a reduction in alpha-motor neurons in the lumbar spinal cord, with significant presynaptic morphological alterations. Disorganised myofibrillar patterns, slight z-line streaming and muscle atrophy were also evident in LD animals. In summary, our study offers insight into the neuropathic and myopathic alterations leading to motor deficits in LD.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative transcriptomic analysis of articular cartilage of post-traumatic osteoarthritis models. 创伤后骨关节炎小鼠模型关节软骨的转录组比较分析

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-21 DOI: 10.1242/dmm.050583

Sophie J Gilbert, Jamie Soul, Yao Hao, Hua Lin, Katarzyna A Piróg, Jonathan Coxhead, Krutik Patel, Matt J Barter, David A Young, Emma J Blain

{"title":"Comparative transcriptomic analysis of articular cartilage of post-traumatic osteoarthritis models.","authors":"Sophie J Gilbert, Jamie Soul, Yao Hao, Hua Lin, Katarzyna A Piróg, Jonathan Coxhead, Krutik Patel, Matt J Barter, David A Young, Emma J Blain","doi":"10.1242/dmm.050583","DOIUrl":"10.1242/dmm.050583","url":null,"abstract":"Animal models of post-traumatic osteoarthritis (PTOA) recapitulate the pathological changes observed in human PTOA. Here, skeletally mature C57Bl6 mice were subjected to either rapid-onset non-surgical mechanical rupture of the anterior cruciate ligament (ACL) or to surgical destabilisation of the medial meniscus (DMM). Transcriptome profiling of micro-dissected cartilage at day 7 or day 42 following ACL or DMM procedure, respectively, showed that the two models were comparable and highly correlative. Gene ontology (GO) enrichment analysis identified similarly enriched pathways that were overrepresented by anabolic terms. To address the transcriptome changes more completely in the ACL model, we also performed small RNA sequencing, describing the first microRNA profile of this model. miR-199-5p was amongst the most abundant, yet differentially expressed, microRNAs, and its inhibition in primary human chondrocytes led to a transcriptome response that was comparable to that observed in both human 'OA damaged vs intact cartilage' and murine DMM cartilage datasets. We also experimentally verified CELSR1, GIT1, ECE1 and SOS2 as novel miR-199-5p targets. Together, these data support the use of the ACL rupture model as a non-invasive companion to the DMM model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA sequencing reveals molecular mechanisms of endometriosis lesion development in mice. RNA 测序揭示了小鼠模型中子宫内膜异位症病变发展的新分子机制。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-23 DOI: 10.1242/dmm.050566

Kavita Panir, John E Schjenken, James Breen, Hon Yeung Chan, Erin Greaves, Sarah A Robertson, M Louise Hull

{"title":"RNA sequencing reveals molecular mechanisms of endometriosis lesion development in mice.","authors":"Kavita Panir, John E Schjenken, James Breen, Hon Yeung Chan, Erin Greaves, Sarah A Robertson, M Louise Hull","doi":"10.1242/dmm.050566","DOIUrl":"10.1242/dmm.050566","url":null,"abstract":"Understanding of molecular mechanisms contributing to the pathophysiology of endometriosis, and upstream drivers of lesion formation, remains limited. Using a C57Bl/6 mouse model in which decidualized endometrial tissue is injected subcutaneously in the abdomen of recipient mice, we generated a comprehensive profile of gene expression in decidualized endometrial tissue (n=4), and in endometriosis-like lesions at Day 7 (n=4) and Day 14 (n=4) of formation. High-throughput mRNA sequencing allowed identification of genes and pathways involved in the initiation and progression of endometriosis-like lesions. We observed distinct patterns of gene expression with substantial differences between the lesions and the decidualized endometrium that remained stable across the two lesion timepoints, and showed similarity to transcriptional changes implicated in human endometriosis lesion formation. Pathway enrichment analysis revealed several immune and inflammatory response-associated canonical pathways, multiple potential upstream regulators, and involvement of genes not previously implicated in endometriosis pathogenesis, including IRF2BP2 and ZBTB10, suggesting novel roles in disease progression. Collectively, the provided data will be a useful resource to inform research on the molecular mechanisms contributing to endometriosis-like lesion development in this mouse model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention? 炎症性肠病中的免疫代谢和线粒体：治疗干预的作用？

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-17 DOI: 10.1242/dmm.050895

Claire E Adams, Duncan G Rutherford, Gareth R Jones, Gwo-Tzer Ho

引用次数: 0

Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. 显性遗传性肌肉疾病：了解其复杂性并探索治疗方法。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-11-06 DOI: 10.1242/dmm.050720

Andrew R Findlay

引用次数: 0