Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper
{"title":"Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model.","authors":"Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper","doi":"10.1242/dmm.050914","DOIUrl":"10.1242/dmm.050914","url":null,"abstract":"<p><p>Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970851","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}
Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck
{"title":"A Drosophila model for mechanistic investigation of tau protein spread.","authors":"Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck","doi":"10.1242/dmm.050858","DOIUrl":"10.1242/dmm.050858","url":null,"abstract":"<p><p>Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau (encoded by MAPT) in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We found age-dependent spread of tau into the brain, represented by detection of tau, but not of GFP. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin (encoded by shi) or knockdown of glycogen synthase kinase-3β (GSK-3β, encoded by sgg). Further work revealed that dynamin promoted tau uptake in recipient tissues, whereas GSK-3β appeared to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau-trafficking components involved in the pathogenesis of neurodegenerative diseases.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343408","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}
Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp
{"title":"The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype.","authors":"Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp","doi":"10.1242/dmm.050771","DOIUrl":"10.1242/dmm.050771","url":null,"abstract":"<p><p>Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin (also known as Cdh1) and upregulation of mesenchymal markers such as N-cadherin (Cdh2) and vimentin (Vim). Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines 4T07, 168FARN and 67NR. We found that 4T1 cells display a hybrid epithelial/mesenchymal phenotype with co-expression of epithelial and mesenchymal markers, whereas 4T07, 168FARN, and 67NR cells display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid epithelial/mesenchymal phenotype that promotes invasion and metastasis.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893109","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}
{"title":"Compromised COPII vesicle trafficking leads to glycogenic hepatopathy.","authors":"Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou","doi":"10.1242/dmm.050748","DOIUrl":"10.1242/dmm.050748","url":null,"abstract":"<p><p>Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975265","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}
Morgan A Giese, Gayathri Ramakrishnan, Laura H Steenberge, Jerome X Dovan, John-Demian Sauer, Anna Huttenlocher
{"title":"Staphylococcus aureus lipid factors modulate melanoma cell clustering and invasion.","authors":"Morgan A Giese, Gayathri Ramakrishnan, Laura H Steenberge, Jerome X Dovan, John-Demian Sauer, Anna Huttenlocher","doi":"10.1242/dmm.050770","DOIUrl":"10.1242/dmm.050770","url":null,"abstract":"<p><p>The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281734","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}
Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert
{"title":"Activation of the heat shock response as a therapeutic strategy for tau toxicity.","authors":"Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert","doi":"10.1242/dmm.050635","DOIUrl":"10.1242/dmm.050635","url":null,"abstract":"<p><p>Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343409","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}
Deena Damschroder, Rubén Zapata-Pérez, Kristin Richardson, Frédéric M Vaz, Riekelt H Houtkooper, Robert Wessells
{"title":"Correction: Stimulating the sir2-spargel axis rescues exercise capacity and mitochondrial respiration in a Drosophila model of Barth syndrome.","authors":"Deena Damschroder, Rubén Zapata-Pérez, Kristin Richardson, Frédéric M Vaz, Riekelt H Houtkooper, Robert Wessells","doi":"10.1242/dmm.052040","DOIUrl":"10.1242/dmm.052040","url":null,"abstract":"","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343410","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}
Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn
{"title":"Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55.","authors":"Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn","doi":"10.1242/dmm.050595","DOIUrl":"https://doi.org/10.1242/dmm.050595","url":null,"abstract":"<p><p>Becker Muscular Dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888756","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}
Seakcheng Lim, Melissa M Mangala, Mira Holliday, Henrietta Cserne Szappanos, Samantha Barratt-Ross, Serena Li, Jordan Thorpe, Whitney Liang, Ginell N Ranpura, Jamie I Vandenberg, Christopher Semsarian, Adam P Hill, Livia C Hool
{"title":"Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.","authors":"Seakcheng Lim, Melissa M Mangala, Mira Holliday, Henrietta Cserne Szappanos, Samantha Barratt-Ross, Serena Li, Jordan Thorpe, Whitney Liang, Ginell N Ranpura, Jamie I Vandenberg, Christopher Semsarian, Adam P Hill, Livia C Hool","doi":"10.1242/dmm.050407","DOIUrl":"10.1242/dmm.050407","url":null,"abstract":"<p><p>Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072319","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}
Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng
{"title":"CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models.","authors":"Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng","doi":"10.1242/dmm.050398","DOIUrl":"10.1242/dmm.050398","url":null,"abstract":"<p><p>Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554350","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}