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
