First person - Masayoshi Ko [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Masayoshi Ko is first author on ‘ Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver’, published in DMM. Masayoshi is an MD and PhD student in the lab of Kenya Kamimura and Shuji Terai at Niigata University, Japan, investigating the involvement of multi-organ linkage via autonomic nerves in non-alcoholic fatty liver (NAFLD)....
Source: DMM Disease Models and Mechanisms - March 28, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 28, 2021 Category: Biomedical Science Authors: Ko, M., Kamimura, K., Owaki, T., Nagoya, T., Sakai, N., Nagayama, I., Niwa, Y., Shibata, O., Oda, C., Morita, S., Kimura, A., Inoue, R., Setsu, T., Sakamaki, A., Yokoo, T., Terai, S. Tags: Metabolic Disorders RESEARCH ARTICLE Source Type: research

Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease [REVIEW]
ABSTRACT Birth defects contribute to ~0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genet...
Source: DMM Disease Models and Mechanisms - March 28, 2021 Category: Biomedical Science Authors: Rufaihah, A. J., Chen, C. K., Yap, C. H., Mattar, C. N. Z. Tags: Developmental Disorders REVIEW Source Type: research

Hyperuricemia causes kidney damage by promoting autophagy and NLRP3-mediated inflammation in rats with urate oxidase deficiency [RESEARCH ARTICLE]
In conclusion, the UOX-KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3-dependent inflammation are critically involved in the development of renal damage and, therefore, highlight the inhibition of autophagy and inflammation in search of therapeutic strategies to treat uric acid nephropathy. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 24, 2021 Category: Biomedical Science Authors: Wu, M., Ma, Y., Chen, X., Liang, N., Qu, S., Chen, H. Tags: Rat as a Disease Model RESEARCH ARTICLE Source Type: research

First person - Paco Lopez-Cuevas [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Paco López-Cuevas is first author on ‘Transformed notochordal cells trigger chronic wounds in zebrafish, destabilizing the vertebral column and bone homeostasis’, published in DMM. Paco is a PhD student in the lab of Paul Martin at the University of Bristol, Bristol, UK, investigating the role of inflammation in cancer progression. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 19, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Transformed notochordal cells trigger chronic wounds in zebrafish, destabilizing the vertebral column and bone homeostasis [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 19, 2021 Category: Biomedical Science Authors: Lopez-Cuevas, P., Deane, L., Yang, Y., Hammond, C. L., Kague, E. Tags: Developmental Disorders, Zebrafish as a Disease Model RESEARCH ARTICLE Source Type: research

First person - Manh Tin Ho and Jiongming Lu [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Manh Tin Ho and Jiongming Lu are co-first authors on ‘A translation-independent activity of PheRS activates growth and proliferation in Drosophila’, published in DMM. Manh Tin conducted the research described in this article while a PhD student in the lab of Beat Suter at the University of Bern, Bern, Switzerland, and is now a postdoctoral researcher in the lab of Daniel Fuster at the University o...
Source: DMM Disease Models and Mechanisms - March 18, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

First person - Mugagga Kalyesubula and Ramgopal Mopuri [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Mugagga Kalyesubula and Ramgopal Mopuri are co-first authors on ‘High-dose vitamin B1 therapy prevents the development of experimental fatty liver driven by overnutrition’, published in DMM. Mugagga is a PhD student in the lab of Dr Hay Dvir at the Volcani Center – Agricultural Research Organization (ARO), Rishon LeZion, Israel and The Hebrew University of Jerusalem, Rehovot, Israel, investi...
Source: DMM Disease Models and Mechanisms - March 18, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

High-dose vitamin B1 therapy prevents the development of experimental fatty liver driven by overnutrition [RESEARCH ARTICLE]
This article has an associated First Person interview with the joint first authors of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 18, 2021 Category: Biomedical Science Authors: Kalyesubula, M., Mopuri, R., Asiku, J., Rosov, A., Yosefi, S., Edery, N., Bocobza, S., Moallem, U., Dvir, H. Tags: Metabolic Disorders RESEARCH ARTICLE Source Type: research

A translation-independent function of PheRS activates growth and proliferation in Drosophila [RESEARCH ARTICLE]
This article has an associated First Person interview with the joint first authors of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 18, 2021 Category: Biomedical Science Authors: Ho, M. T., Lu, J., Brunssen, D., Suter, B. Tags: Drosophila as a Disease Model RESEARCH ARTICLE Source Type: research

Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation [RESEARCH ARTICLE]
ABSTRACT Myeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined. Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we do...
Source: DMM Disease Models and Mechanisms - March 18, 2021 Category: Biomedical Science Authors: Dobosz, E., Lorenz, G., Ribeiro, A., Würf, V., Wadowska, M., Kotlinowski, J., Schmaderer, C., Potempa, J., Fu, M., Koziel, J., Lech, M. Tags: RESEARCH ARTICLE Source Type: research

First person - Aikta Sharma [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Aikta Sharma is first author on ‘Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition’, published in DMM. Aikta is a PhD student in the lab of Dr Claire E. Clarkin at the University of Southampton, Southampton, UK, investigating the role of osteoblast-derived vascular endothelial growth factor in bone matrix formation. (Source:...
Source: DMM Disease Models and Mechanisms - March 17, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition [RESOURCE ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 17, 2021 Category: Biomedical Science Authors: Sharma, A., Goring, A., Johnson, P. B., Emery, R. J. H., Hesse, E., Boyde, A., Olsen, B. R., Pitsillides, A. A., Oreffo, R. O. C., Mahajan, S., Clarkin, C. E. Tags: RESOURCE ARTICLE Source Type: research

First person - Ralitsa Madsen [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Ralitsa Madsen is first author on ‘NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells’, published in DMM. Ralitsa conducted the research described in this article while a member of Prof. Robert Semple's lab, initially as a PhD student at the Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic R...
Source: DMM Disease Models and Mechanisms - March 11, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

NODAL/TGF{beta} signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - March 11, 2021 Category: Biomedical Science Authors: Madsen, R. R., Longden, J., Knox, R. G., Robin, X., Völlmy, F., Macleod, K. G., Moniz, L. S., Carragher, N. O., Linding, R., Vanhaesebroeck, B., Semple, R. K. Tags: Stem Cells RESEARCH ARTICLE Source Type: research

EZH2 is required for parathyroid and thymic development through differentiation of the third pharyngeal pouch endoderm [RESEARCH ARTICLE]
In this study, we investigated whether EZH2 has a role in the development of the pharyngeal apparatus and whether it regulates the expression of the Tbx1 gene, which encodes a key transcription factor required in pharyngeal development. To these ends, we performed genetic in vivo experiments with mouse embryos and used mouse embryonic stem cell (ESC)-based protocols to probe endoderm and cardiogenic mesoderm differentiation. Results showed that EZH2 occupies the Tbx1 gene locus in mouse embryos, and that suppression of EZH2 was associated with reduced expression of Tbx1 in differentiated mouse ESCs. Conditional deletion of...
Source: DMM Disease Models and Mechanisms - March 11, 2021 Category: Biomedical Science Authors: Caprio, C., Lania, G., Bilio, M., Ferrentino, R., Chen, L., Baldini, A. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

Modelling epilepsy in the mouse: challenges and solutions [REVIEW]
ABSTRACT In most mouse models of disease, the outward manifestation of a disorder can be measured easily, can be assessed with a trivial test such as hind limb clasping, or can even be observed simply by comparing the gross morphological characteristics of mutant and wild-type littermates. But what if we are trying to model a disorder with a phenotype that appears only sporadically and briefly, like epileptic seizures? The purpose of this Review is to highlight the challenges of modelling epilepsy, in which the most obvious manifestation of the disorder, seizures, occurs only intermittently, possibly very rarely and often ...
Source: DMM Disease Models and Mechanisms - March 1, 2021 Category: Biomedical Science Authors: Marshall, G. F., Gonzalez-Sulser, A., Abbott, C. M. Tags: Developmental Disorders, Tools and Resources for Mouse Studies REVIEW Source Type: research

Altered cytoskeletal arrangement in induced pluripotent stem cells and motor neurons from patients with riboflavin transporter deficiency [RESEARCH ARTICLE]
ABSTRACT The cytoskeletal network plays a crucial role in the differentiation, morphogenesis, function and homeostasis of the nervous tissue, so that alterations in any of its components may lead to neurodegenerative diseases. Riboflavin transporter deficiency (RTD), a childhood-onset disorder characterized by degeneration of motor neurons (MNs), is caused by biallelic mutations in genes encoding the human riboflavin (RF) transporters. In a patient-specific induced pluripotent stem cells (iPSCs) model of RTD, we recently demonstrated altered cell-cell contacts, energy dysmetabolism and redox imbalance. The present study fo...
Source: DMM Disease Models and Mechanisms - February 24, 2021 Category: Biomedical Science Authors: Niceforo, A., Marioli, C., Colasuonno, F., Petrini, S., Massey, K., Tartaglia, M., Bertini, E., Moreno, S., Compagnucci, C. Tags: Stem Cells RESEARCH ARTICLE Source Type: research

The infantile myofibromatosis NOTCH3 L1519P mutation leads to hyperactivated ligand-independent Notch signaling and increased PDGFRB expression [RESEARCH ARTICLE]
In this study, we address the molecular consequences of the NOTCH3L1519P mutation and the relationship between Notch and PDGFRB signaling in IMF. The NOTCH3L1519P receptor generates enhanced downstream signaling in a ligand-independent manner. Despite the enhanced signaling, the NOTCH3L1519P receptor is absent from the cell surface and instead accumulates in the endoplasmic reticulum. Furthermore, the localization of the NOTCH3L1519P receptor in the bipartite, heterodimeric state is altered, combined with avid secretion of the mutated extracellular domain from the cell. Chloroquine treatment strongly reduces the amount of ...
Source: DMM Disease Models and Mechanisms - February 24, 2021 Category: Biomedical Science Authors: Wu, D., Wang, S., Oliveira, D. V., Del Gaudio, F., Vanlandewijck, M., Lebouvier, T., Betsholtz, C., Zhao, J., Jin, S., Lendahl, U., Karlström, H. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies [REVIEW]
ABSTRACT Bronchopulmonary dysplasia (BPD) is a chronic lung disease caused by exposure to high levels of oxygen (hyperoxia) and is the most common complication that affects preterm newborns. At present, there is no cure for BPD. Infants can recover from BPD; however, they will suffer from significant morbidity into adulthood in the form of neurodevelopmental impairment, asthma and emphysematous changes of the lung. The development of hyperoxia-induced lung injury models in small and large animals to test potential treatments for BPD has shown some success, yet a lack of standardization in approaches and methods makes clini...
Source: DMM Disease Models and Mechanisms - February 23, 2021 Category: Biomedical Science Authors: Giusto, K., Wanczyk, H., Jensen, T., Finck, C. Tags: REVIEW Source Type: research

The twin pillars of Disease Models & Mechanisms [EDITORIAL]
(Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - February 22, 2021 Category: Biomedical Science Authors: Patton,, E. E. Tags: EDITORIAL Source Type: research

Modeling the developmental origins of pediatric cancer to improve patient outcomes [PERSPECTIVE]
ABSTRACT In the treatment of children and adolescents with cancer, multimodal approaches combining surgery, chemotherapy and radiation can cure most patients, but may cause lifelong health problems in survivors. Current therapies only modestly reflect increased knowledge about the molecular mechanisms of these cancers. Advances in next-generation sequencing have provided unprecedented cataloging of genetic aberrations in tumors, but understanding how these genetic changes drive cellular transformation, and how they can be effectively targeted, will require multidisciplinary collaboration and preclinical models that are tru...
Source: DMM Disease Models and Mechanisms - February 22, 2021 Category: Biomedical Science Authors: Amatruda, J. F. Tags: Cancer, Developmental Disorders, Model Systems in Drug Discovery PERSPECTIVE Source Type: research

Cardiovascular phenotype of the Dmdmdx rat - a suitable animal model for Duchenne muscular dystrophy [RESEARCH ARTICLE]
ABSTRACT Besides skeletal muscle abnormalities, Duchenne muscular dystrophy (DMD) patients present with dilated cardiomyopathy development, which considerably contributes to morbidity and mortality. Because the mechanisms responsible for the cardiac complications in the context of DMD are largely unknown, evidence-based therapy approaches are still lacking. This has increased the need for basic research efforts into animal models for DMD. Here, we characterized in detail the cardiovascular abnormalities of Dmdmdx rats, with the aim of determining the suitability of this recently established dystrophin-deficient small anima...
Source: DMM Disease Models and Mechanisms - February 22, 2021 Category: Biomedical Science Authors: Szabo, P. L., Ebner, J., Koenig, X., Hamza, O., Watzinger, S., Trojanek, S., Abraham, D., Todt, H., Kubista, H., Schicker, K., Remy, S., Anegon, I., Kiss, A., Podesser, B. K., Hilber, K. Tags: Rat as a Disease Model, Neuromuscular RESEARCH ARTICLE Source Type: research

A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities [RESEARCH ARTICLE]
ABSTRACT Activin/myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules, which result in augmenting muscle growth. However, these molecules, in particular activin, play major roles in tissue homeostasis in numerous organs of the mammalian body. We have recently shown that although the attenuation of activin/myostatin results in robust muscle growth, it also has a detrimental impact on the testis. Here, we aim...
Source: DMM Disease Models and Mechanisms - February 19, 2021 Category: Biomedical Science Authors: Vaughan, D., Mitchell, R., Kretz, O., Chambers, D., Lalowski, M., Amthor, H., Ritvos, O., Pasternack, A., Matsakas, A., Vaiyapuri, S., Huber, T. B., Denecke, B., Mukherjee, A., Widera, D., Patel, K. Tags: Neuromuscular RESEARCH ARTICLE Source Type: research

Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice [RESEARCH ARTICLE]
ABSTRACT Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand the mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+/J (C3H) and DBA/2J-Gpnmb+ (D2-G) mouse strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ ...
Source: DMM Disease Models and Mechanisms - February 19, 2021 Category: Biomedical Science Authors: Tolman, N. G., Balasubramanian, R., Macalinao, D. G., Kearney, A. L., MacNicoll, K. H., Montgomery, C. L., de Vries, W. N., Jackson, I. J., Cross, S. H., Kizhatil, K., Nair, K. S., John, S. W. M. Tags: RESEARCH ARTICLE Source Type: research

First person - Frederike Riemslagh [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Frederike Riemslagh is first author on ‘Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice’, published in DMM. Frederike conducted the research described in this article while a PhD Candidate in Prof. Dr Rob Willemse's lab at Erasmus Medical Center, Department of Clinical Genetics, Rotterdam, The Netherlan...
Source: DMM Disease Models and Mechanisms - February 16, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice [RESEARCH ARTICLE]
In conclusion, expression of 36x pure G4C2 repeats including 100-bp human flanking regions is sufficient for RAN translation of sense DPRs, and evokes a functional locomotor phenotype. Our inducible mouse model suggests that early diagnosis and treatment are important for C9FTD/ALS patients. This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - February 16, 2021 Category: Biomedical Science Authors: Riemslagh, F. W., van der Toorn, E. C., Verhagen, R. F. M., Maas, A., Bosman, L. W. J., Hukema, R. K., Willemsen, R. Tags: Neurodegenerative disorders, Neuromuscular RESEARCH ARTICLE Source Type: research

Hearing impairment due to Mir183/96/182 mutations suggests both loss-of-function and gain-of-function effects [RESEARCH ARTICLE]
ABSTRACT The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183, but the roles of these closely-linked microRNAs are as yet unknown. Here, we analyse mice carrying null alleles of Mir182, and of Mir183 and Mir96 together to investigate their roles in hearing. We found that Mir183/96 heterozygous mice had normal hearing and homozygotes were completely deaf with abnormal hair cell stereocilia bundles and reduced numbers of inner hair cell synapses at 4 weeks of age. Mir182 knockout m...
Source: DMM Disease Models and Mechanisms - February 14, 2021 Category: Biomedical Science Authors: Lewis, M. A., Di Domenico, F., Ingham, N. J., Prosser, H. M., Steel, K. P. Tags: RESEARCH ARTICLE Source Type: research

First person - Pranidhi Baddam [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Pranidhi Baddam is first author on ‘Neural crest-specific loss of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction and disordered breathing, modeling obstructive sleep apnea’, published in DMM. Pranidhi is a PhD student in the lab of Daniel Graf at the University of Alberta, Edmonton, Canada, investigating the contribution of different types of cartilage to midfacial growth. (Source: D...
Source: DMM Disease Models and Mechanisms - February 11, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

RET inhibition in novel patient-derived models of RET fusion- positive lung adenocarcinoma reveals a role for MYC upregulation [RESEARCH ARTICLE]
ABSTRACT Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here, we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-d...
Source: DMM Disease Models and Mechanisms - February 11, 2021 Category: Biomedical Science Authors: Hayashi, T., Odintsov, I., Smith, R. S., Ishizawa, K., Liu, A. J. W., Delasos, L., Kurzatkowski, C., Tai, H., Gladstone, E., Vojnic, M., Kohsaka, S., Suzawa, K., Liu, Z., Kunte, S., Mattar, M. S., Khodos, I., Davare, M. A., Drilon, A., Cheng, E., de Stanc Tags: Cancer RESEARCH ARTICLE Source Type: research

Neural crest-specific loss of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction and disordered breathing, modeling obstructive sleep apnea [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - February 11, 2021 Category: Biomedical Science Authors: Baddam, P., Biancardi, V., Roth, D. M., Eaton, F., Thereza-Bussolaro, C., Mandal, R., Wishart, D. S., Barr, A., MacLean, J., Flores-Mir, C., Pagliardini, S., Graf, D. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy [RESEARCH ARTICLE]
ABSTRACT Mislocalization of the TAR DNA-binding protein 43 (TDP-43; encoded by TARDBP) from the nucleus to the cytoplasm is a common feature of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects of this mislocalization are not well understood. To investigate the impact of mislocalized TDP-43 on neuronal cell bodies, axons and axonal terminals, we utilized the mouse visual system to create a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinal ganglion cells (RGCs) were transduced with GFP-tagged human wild-typ...
Source: DMM Disease Models and Mechanisms - February 11, 2021 Category: Biomedical Science Authors: Atkinson, R., Leung, J., Bender, J., Kirkcaldie, M., Vickers, J., King, A. Tags: Neurodegenerative disorders RESEARCH ARTICLE Source Type: research

The latest from the preLights community - January 2021 [PREPRINT HIGHLIGHTS]
(Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - February 8, 2021 Category: Biomedical Science Tags: PREPRINT HIGHLIGHTS Source Type: research

Mutant non-coding RNA resource in mouse embryonic stem cells [RESOURCE ARTICLE]
ABSTRACT Gene trapping is a high-throughput approach that has been used to introduce insertional mutations into the genome of mouse embryonic stem (ES) cells. It is performed with generic gene trap vectors that simultaneously mutate and report the expression of the endogenous gene at the site of insertion and provide a DNA sequence tag for the rapid identification of the disrupted gene. Large-scale international efforts assembled a gene trap library of 566,554 ES cell lines with single gene trap integrations distributed throughout the genome. Here, we re-investigated this unique library and identified mutations in 2202 non...
Source: DMM Disease Models and Mechanisms - February 5, 2021 Category: Biomedical Science Authors: Hansen, J., von Melchner, H., Wurst, W. Tags: Stem Cells, Tools and Resources for Mouse Studies RESOURCE ARTICLE Source Type: research

AIRE deficiency, from preclinical models to human APECED disease [REVIEW]
ABSTRACT Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare life-threatening autoimmune disease that attacks multiple organs and has its onset in childhood. It is an inherited condition caused by a variety of mutations in the autoimmune regulator (AIRE) gene that encodes a protein whose function has been uncovered by the generation and study of Aire-KO mice. These provided invaluable insights into the link between AIRE expression in medullary thymic epithelial cells (mTECs), and the broad spectrum of self-antigens that these cells express and present to the developing thymocytes. However, the...
Source: DMM Disease Models and Mechanisms - February 5, 2021 Category: Biomedical Science Authors: Besnard, M., Padonou, F., Provin, N., Giraud, M., Guillonneau, C. Tags: REVIEW Source Type: research

First person - Talia Nasr [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Talia Nasr is first author on ‘Disruption of a Hedgehog-Foxf1-Rspo2 signaling axis leads to tracheomalacia and a loss of Sox9+ tracheal chondrocytes’, published in DMM. Talia is a MD/PhD student at the University of Cincinnati, USA, currently in the final two MD years, with the PhD work completed in the lab of Aaron Zorn, investigating the pathogenesis of congenital tracheoesophageal defects. (Sou...
Source: DMM Disease Models and Mechanisms - February 4, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

Disruption of a Hedgehog-Foxf1-Rspo2 signaling axis leads to tracheomalacia and a loss of Sox9+ tracheal chondrocytes [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - February 4, 2021 Category: Biomedical Science Authors: Nasr, T., Holderbaum, A. M., Chaturvedi, P., Agarwal, K., Kinney, J. L., Daniels, K., Trisno, S. L., Ustiyan, V., Shannon, J. M., Wells, J. M., Sinner, D., Kalinichenko, V. V., Zorn, A. M. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

First person - Karen Lange [FIRST PERSON]
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Karen Lange is first author on ‘Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans’, published in DMM. Karen is a postdoc in the lab of Oliver Blacque at University College Dublin, Dublin, Ireland, using genome-editing techniques in worms to investigate ciliopathies, rare genetic disorders caused by defects in cilia. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - January 26, 2021 Category: Biomedical Science Tags: FIRST PERSON Source Type: research

The darkness and the light: diurnal rodent models for seasonal affective disorder [REVIEW]
ABSTRACT The development of animal models is a critical step for exploring the underlying pathophysiological mechanisms of major affective disorders and for evaluating potential therapeutic approaches. Although most neuropsychiatric research is performed on nocturnal rodents, differences in how diurnal and nocturnal animals respond to changing photoperiods, combined with a possible link between circadian rhythm disruption and affective disorders, has led to a call for the development of diurnal animal models. The need for diurnal models is most clear for seasonal affective disorder (SAD), a widespread recurrent depressive ...
Source: DMM Disease Models and Mechanisms - January 26, 2021 Category: Biomedical Science Authors: Shankar, A., Williams, C. T. Tags: Rat as a Disease Model REVIEW Source Type: research

Resolving the heterogeneity of diaphragmatic mesenchyme: a novel mouse model of congenital diaphragmatic hernia [RESEARCH ARTICLE]
ABSTRACT Congenital diaphragmatic hernia (CDH) is a relatively common developmental defect with considerable mortality and morbidity. Formation of the diaphragm is a complex process that involves several cell types, each with different developmental origins. Owing to this complexity, the aetiology of CDH is not well understood. The pleuroperitoneal folds (PPFs) and the posthepatic mesenchymal plate (PHMP) are transient structures that are essential during diaphragm development. Using several mouse models, including lineage tracing, we demonstrate the heterogeneous nature of the cells that make up the PPFs. The conditional ...
Source: DMM Disease Models and Mechanisms - January 26, 2021 Category: Biomedical Science Authors: Cleal, L., McHaffie, S. L., Lee, M., Hastie, N., Martinez-Estrada, O. M., Chau, Y.-Y. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans [RESEARCH ARTICLE]
This article has an associated First Person interview with the first author of the paper. (Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - January 26, 2021 Category: Biomedical Science Authors: Lange, K. I., Tsiropoulou, S., Kucharska, K., Blacque, O. E. Tags: Rare diseases, Developmental Disorders, C. elegans RESEARCH ARTICLE Source Type: research

Mutant Cx30-A88V mice exhibit hydrocephaly and sex-dependent behavioral abnormalities, implicating a functional role for Cx30 in the brain [RESEARCH ARTICLE]
ABSTRACT Connexin 30 (Cx30; also known as Gjb6 when referring to the mouse gene) is expressed in ependymal cells of the brain ventricles, in leptomeningeal cells and in astrocytes rich in connexin 43 (Cx43), leading us to question whether patients harboring GJB6 mutations exhibit any brain anomalies. Here, we used mice harboring the human disease-associated A88V Cx30 mutation to address this gap in knowledge. Brain Cx30 levels were lower in male and female Cx30A88V/A88V mice compared with Cx30A88V/+ and Cx30+/+ mice, whereas Cx43 levels were lower only in female Cx30 mutant mice. Characterization of brain morphology reveal...
Source: DMM Disease Models and Mechanisms - January 26, 2021 Category: Biomedical Science Authors: Novielli-Kuntz, N. M., Press, E. R., Barr, K., Prado, M. A. M., Laird, D. W. Tags: Developmental Disorders RESEARCH ARTICLE Source Type: research

From its roots come branches and growth for Disease Models & Mechanisms [EDITORIAL]
(Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - January 24, 2021 Category: Biomedical Science Authors: Justice, M. J. Tags: EDITORIAL Source Type: research

Haematopoietic ageing through the lens of single-cell technologies [REVIEW]
ABSTRACT Human lifespan is now longer than ever and, as a result, modern society is getting older. Despite that, the detailed mechanisms behind the ageing process and its impact on various tissues and organs remain obscure. In general, changes in DNA, RNA and protein structure throughout life impair their function. Haematopoietic ageing refers to the age-related changes affecting a haematopoietic system. Aged blood cells display different functional aberrations depending on their cell type, which might lead to the development of haematologic disorders, including leukaemias, anaemia or declining immunity. In contrast to tra...
Source: DMM Disease Models and Mechanisms - January 22, 2021 Category: Biomedical Science Authors: Strzelecka, P. M., Damm, F. Tags: Stem Cells REVIEW Source Type: research

Mistargeting of secretory cargo in retromer-deficient cells [RESEARCH ARTICLE]
ABSTRACT Intracellular trafficking is a basic and essential cellular function required for delivery of proteins to the appropriate subcellular destination; this process is especially demanding in professional secretory cells, which synthesize and secrete massive quantities of cargo proteins via regulated exocytosis. The Drosophila larval salivary glands are composed of professional secretory cells that synthesize and secrete mucin proteins at the onset of metamorphosis. Using the larval salivary glands as a model system, we have identified a role for the highly conserved retromer complex in trafficking of secretory granule...
Source: DMM Disease Models and Mechanisms - January 22, 2021 Category: Biomedical Science Authors: Neuman, S. D., Terry, E. L., Selegue, J. E., Cavanagh, A. T., Bashirullah, A. Tags: Neurodegenerative disorders, Drosophila as a Disease Model RESEARCH ARTICLE Source Type: research

Sensory neuron cultures derived from adult db/db mice as a simplified model to study type-2 diabetes-associated axonal regeneration defects [RESEARCH ARTICLE]
ABSTRACT Diabetic neuropathy (DN) is an early common complication of diabetes mellitus (DM), leading to chronic pain, sensory loss and muscle atrophy. Owing to its multifactorial etiology, neuron in vitro cultures have been proposed as simplified systems for DN studies. However, the most used models currently available do not recreate the chronic and systemic damage suffered by peripheral neurons of type-2 DM (T2DM) individuals. Here, we cultured neurons derived from dorsal root ganglia from 6-month-old diabetic db/db-mice, and evaluated their morphology by the Sholl method as an easy-to-analyze readout of neuronal functio...
Source: DMM Disease Models and Mechanisms - January 22, 2021 Category: Biomedical Science Authors: De Gregorio, C., Ezquer, F. Tags: Metabolic Disorders RESEARCH ARTICLE Source Type: research

Head-to-head study of oxelumab and adalimumab in a mouse model of ulcerative colitis based on NOD/Scid IL2R{gamma}null mice reconstituted with human peripheral blood mononuclear cells [RESEARCH ARTICLE]
This study's aim was to demonstrate that the combination of patient immune profiling and testing in a humanized mouse model of ulcerative colitis (UC) might lead to patient stratification for treatment with oxelumab. First, immunological profiles of UC patients and non-UC donors were analyzed for CD4+ T cells expressing OX40 (CD134; also known as TNFRSF4) and CD14+ monocytes expressing OX40L (CD252; also known as TNFSF4) by flow cytometric analysis. A significant difference was observed between the groups for CD14+ OX40L+ (UC: n=11, 85.44±21.17, mean±s.d.; non-UC: n=5, 30.7±34.92; P=0.02), whereas no s...
Source: DMM Disease Models and Mechanisms - January 21, 2021 Category: Biomedical Science Authors: Jodeleit, H., Winkelmann, P., Caesar, J., Sterz, S., Holdt, L. M., Beigel, F., Stallhofer, J., Breiteneicher, S., Bartnik, E., Leeuw, T., Siebeck, M., Gropp, R. Tags: Model Systems in Drug Discovery RESEARCH ARTICLE Source Type: research

Heterogeneity in clone dynamics within and adjacent to intestinal tumours identified by Dre-mediated lineage tracing [RESEARCH ARTICLE]
ABSTRACT Somatic models of tissue pathology commonly use induction of gene-specific mutations in mice mediated by spatiotemporal regulation of Cre recombinase. Subsequent investigation of the onset and development of disease can be limited by the inability to track changing cellular behaviours over time. Here, a lineage-tracing approach based on ligand-dependent activation of Dre recombinase that can be employed independently of Cre is described. The clonal biology of the intestinal epithelium following Cre-mediated stabilisation of β-catenin reveals that, within tumours, many new clones rapidly become extinct. Surviv...
Source: DMM Disease Models and Mechanisms - January 15, 2021 Category: Biomedical Science Authors: Thorsen, A.-S., Khamis, D., Kemp, R., Colombe, M., Lourenco, F. C., Morrissey, E., Winton, D. Tags: Cancer RESEARCH ARTICLE Source Type: research

Correction: A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice [CORRECTION]
(Source: DMM Disease Models and Mechanisms)
Source: DMM Disease Models and Mechanisms - January 11, 2021 Category: Biomedical Science Authors: Abdelhamed, Z., Lukacs, M., Cindric, S., Ali, S., Omran, H., Stottmann, R. W. Tags: Developmental Disorders CORRECTION Source Type: research

Regulation of murine copper homeostasis by members of the COMMD protein family [RESEARCH ARTICLE]
In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of...
Source: DMM Disease Models and Mechanisms - January 7, 2021 Category: Biomedical Science Authors: Singla, A., Chen, Q., Suzuki, K., Song, J., Fedoseienko, A., Wijers, M., Lopez, A., Billadeau, D. D., van de Sluis, B., Burstein, E. Tags: RESEARCH ARTICLE Source Type: research