Neuropathology of Mowat–Wilson Syndrome

2020 ◽  
Vol 23 (4) ◽  
pp. 322-325
Author(s):  
Miriam R. Conces ◽  
Anna Hughes ◽  
Christopher R. Pierson
Keyword(s):  
Mouse Models ◽  
Hirschsprung Disease ◽  
Genetically Engineered ◽  
Facial Dysmorphism ◽  
Genetically Engineered Mouse Models ◽  
Brain Malformations ◽  
Neuroimaging Data ◽  
The Brain ◽  
Correlate Data

Mowat–Wilson syndrome (MWS) is a syndromic form of Hirschsprung disease that is characterized by variable degrees of intellectual disability, characteristic facial dysmorphism, and a diverse set of other congenital malformations due to haploinsufficiency of ZEB2. A variety of brain malformations have been described in neuroimaging studies of MWS patients, and the role of ZEB2 in the brain has been studied in a multitude of genetically engineered mouse models that are now available. However, a paucity of autopsy information limits our ability to correlate data from neuroimaging studies and animal models with actual MWS patient tissues. Here, we report the autopsy neuropathology of a 19-year-old male patient with MWS. Autopsy neuropathology findings correlated well with the reported MWS neuroimaging data and are in keeping with data from genetically engineered MWS mouse models. This autopsy enhances our understanding of ZEB2 function in human brain development and demonstrates the reliability of MWS murine models.

scholarly journals TMIC-25. DISSECTING THE ROLE OF HOST GENETICS IN GLIOMA EVOLUTION USING GENETICALLY-ENGINEERED MOUSE MODELS AND THE COLLABORATIVE CROSS

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi261-vi261
Author(s):  
Kasey Skinner ◽  
Martin Ferris ◽  
Ryan Bash ◽  
Abigail Shelton ◽  
Erin Smithberger ◽  
...  
Keyword(s):  
Mouse Models ◽  
Genetically Engineered ◽  
Collaborative Cross ◽  
Host Genetics ◽  
Genetically Engineered Mouse Models

scholarly journals Oxidative Stress in Genetic Mouse Models of Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-25 ◽  
Author(s):  
Mustafa Varçin ◽  
Eduard Bentea ◽  
Yvette Michotte ◽  
Sophie Sarre
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Models ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Gene Environment ◽  
Disease Associated Genes ◽  
Genetic Mouse Models

There is extensive evidence in Parkinson’s disease of a link between oxidative stress and some of the monogenically inherited Parkinson’s disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson’s disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson’s disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson’s disease, gene-environment interactions in genetically engineered mouse models of Parkinson’s disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson’s disease.

scholarly journals Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

2018 ◽  
Author(s):  
Mathilde Soulez ◽  
Marc K. Saba-El-Leil ◽  
Benjamin Turgeon ◽  
Simon Mathien ◽  
Philippe Coulombe ◽  
...  
Keyword(s):  
Mouse Models ◽  
Kinase Activity ◽  
Growth Curves ◽  
Perinatal Period ◽  
Genetically Engineered ◽  
Mutant Mice ◽  
Lung Maturation ◽  
Genetically Engineered Mouse Models ◽  
Perinatal Lethality

AbstractThe physiological functions of the atypical MAP kinase ERK3 remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6lacZ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically-inactive (Mapk6KD) or conditional (Mapk6Δ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is ncessary for optimal post-natal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that expression of several Mapk6 neighboring genes is deregulated in Mapk6lacZ mice, but not in Mapk6KD or Mapk6Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are likely to be responsible for the perinatal lethality phenotype of Mapk6lacZ mutant mice.

scholarly journals DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR ACVR1 AND PIK3CA MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINE GLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii295-iii295
Author(s):  
Annette Wu ◽  
Tak Mak ◽  
Jerome Fortin
Keyword(s):  
Mouse Models ◽  
Pik3ca Mutation ◽  
Cell Lineage ◽  
Gene Expression Signature ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Dismal Prognosis ◽  
Human Pathology ◽  
Genes Encoding ◽  
Mechanistic Basis

Abstract Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we generated genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M, and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without (“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages of gliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes encoding transcription factors (TFs) with dual roles in controlling glial and neuronal differentiation were upregulated in tumors. Some of these genes were mildly induced by Acvr1G328V alone. Functional experiments using CRISPR/Cas9-mediated gene editing in patient-derived cell lines confirmed a role for some of these TFs in controlling DMG cell fitness. Overall, our results suggest that Pik3caH1047R consolidates Acvr1G328V-induced glial differentiation arrest to drive DMG development and progression.

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

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