scholarly journals A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

2020 ◽  
Author(s):  
Jiayang Chen ◽  
Mary E. Lambo ◽  
Xia Ge ◽  
Joshua T. Dearborn ◽  
Yating Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Brain Development ◽  
Human Genetics ◽  
Preclinical Studies ◽  
Loss Of Function ◽  
Gene Target ◽  
Brain Anomalies ◽  
Physiological Properties ◽  
Insight Into ◽  
Target Activation

AbstractHuman genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. Studies during brain development reveal disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and highlight precocious neuronal differentiation as the mechanism for microcephaly. In contrast, adult studies reveal that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral features including hyperactivity, hypotonia, and social alterations, with more severe phenotypes in males. Overall, these studies provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

Hematopoietic defects in the Ts1Cje mouse model of Down syndrome

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 1929-1937 ◽  
Author(s):  
Catherine L. Carmichael ◽  
Ian J. Majewski ◽  
Warren S. Alexander ◽  
Donald Metcalf ◽  
Douglas J. Hilton ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Cell Function ◽  
Fetal Liver ◽  
Partial Trisomy ◽  
Chromosome 21 ◽  
Loss Of Function ◽  
Premalignant Disease ◽  
Acute Megakaryocytic Leukemia ◽  
Insight Into

Down syndrome (DS) persons are born with various hematopoietic abnormalities, ranging from relatively benign, such as neutrophilia and macrocytosis, to a more severe transient myeloproliferative disorder (TMD). In most cases, these abnormalities resolve in the first few months to years of life. However, sometimes the TMD represents a premalignant disease that develops into acute megakaryocytic leukemia (AMKL), usually in association with acquired GATA1 mutations. To gain insight into the mechanisms responsible for these abnormalities, we analyzed the hematopoietic development of the Ts1Cje mouse model of DS. Our analyses identified defects in mature blood cells, including macrocytosis and anemia, as well as abnormalities in fetal liver and bone marrow stem and progenitor cell function. Despite these defects, the Ts1Cje mice do not develop disease resembling either TMD or AMKL, and this was not altered by a loss of function allele of Gata1. Thus, loss of Gata1 and partial trisomy of chromosome 21 orthologs, when combined, do not appear to be sufficient to induce TMD or AMKL-like phenotypes in mice.

scholarly journals Mouse Models ofGNAO1-Associated Movement Disorder: Allele- and sex-specific differences in phenotypes

2018 ◽  
Author(s):  
Huijie Feng ◽  
Casandra L. Larrivee ◽  
Elena Demireva ◽  
Huirong Xie ◽  
Jeff Leipprandt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Movement Disorder ◽  
Movement Disorders ◽  
Mutant Mouse ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Normal Function ◽  
Preclinical Studies ◽  
Loss Of Function ◽  
Males And Females

AbstractBackgroundInfants and children with dominantde novomutations inGNAO1exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutantGNAO1allele.ObjectivesHere we develop a mouse model carrying a humanGNAO1mutation and determine whether clinical features of theGNAO1mutation including movement disorder would be evident in the mouse model.MethodsA mouseGnao1knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S) was also studied for comparison.ResultsGnao1+/G203Rmutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. MaleGnao1+/G203Rmice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. MaleGnao1+/G203Rmice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.ConclusionsGnao1+/G203Rmice phenocopy children with heterozygousGNAO1G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies ofGNAO1-related movement disorders.

scholarly journals Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 470
Author(s):  
Jeremy W. Prokop ◽  
Caleb P. Bupp ◽  
Austin Frisch ◽  
Stephanie M. Bilinovich ◽  
Daniel B. Campbell ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Progenitor Cells ◽  
Neurodevelopmental Disorder ◽  
Fetal Brain ◽  
Missense Variant ◽  
Neural Progenitor ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Systematic Analysis ◽  
Function Expression

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

scholarly journals Jumping Ahead with Sleeping Beauty: Mechanistic Insights into Cut-and-Paste Transposition

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 76
Author(s):  
Matthias T. Ochmann ◽  
Zoltán Ivics
Keyword(s):  
Genetic Engineering ◽  
Structural Data ◽  
Sleeping Beauty ◽  
Preclinical Studies ◽  
Gene Vector ◽  
Functional Information ◽  
Vector Systems ◽  
Novel Variants ◽  
Insight Into ◽  
Cellular Genome

Sleeping Beauty (SB) is a transposon system that has been widely used as a genetic engineering tool. Central to the development of any transposon as a research tool is the ability to integrate a foreign piece of DNA into the cellular genome. Driven by the need for efficient transposon-based gene vector systems, extensive studies have largely elucidated the molecular actors and actions taking place during SB transposition. Close transposon relatives and other recombination enzymes, including retroviral integrases, have served as useful models to infer functional information relevant to SB. Recently obtained structural data on the SB transposase enable a direct insight into the workings of this enzyme. These efforts cumulatively allowed the development of novel variants of SB that offer advanced possibilities for genetic engineering due to their hyperactivity, integration deficiency, or targeting capacity. However, many aspects of the process of transposition remain poorly understood and require further investigation. We anticipate that continued investigations into the structure–function relationships of SB transposition will enable the development of new generations of transposition-based vector systems, thereby facilitating the use of SB in preclinical studies and clinical trials.

scholarly journals Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vidya C. Sinha ◽  
Amanda L. Rinkenbaugh ◽  
Mingchu Xu ◽  
Xinhui Zhou ◽  
Xiaomei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Mouse Model ◽  
Transition State ◽  
Tumor Cell ◽  
Single Cell ◽  
Tumor Cells ◽  
Breast Lesions ◽  
Aggressive Tumor ◽  
Insight Into

AbstractThere is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.

scholarly journals Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Won Jin Ho ◽  
Rossin Erbe ◽  
Ludmila Danilova ◽  
Zaw Phyo ◽  
Emma Bigelow ◽  
...  
Keyword(s):  
Mouse Model ◽  
Primary Tumors ◽  
Regulatory Pathways ◽  
Tumor Microenvironments ◽  
Clinical Responses ◽  
Cellular Pathways ◽  
Autopsy Specimens ◽  
Rapid Autopsy ◽  
Insight Into ◽  
Systemic Therapies

Abstract Background The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed at the metastatic stage, and standard therapies have limited activity with a dismal 5-year survival rate of only 8%. The liver and lung are the most common sites of PDAC metastasis, and each have been differentially associated with prognoses and responses to systemic therapies. A deeper understanding of the molecular and cellular landscape within the tumor microenvironment (TME) metastasis at these different sites is critical to informing future therapeutic strategies against metastatic PDAC. Results By leveraging combined mass cytometry, immunohistochemistry, and RNA sequencing, we identify key regulatory pathways that distinguish the liver and lung TMEs in a preclinical mouse model of metastatic PDAC. We demonstrate that the lung TME generally exhibits higher levels of immune infiltration, immune activation, and pro-immune signaling pathways, whereas multiple immune-suppressive pathways are emphasized in the liver TME. We then perform further validation of these preclinical findings in paired human lung and liver metastatic samples using immunohistochemistry from PDAC rapid autopsy specimens. Finally, in silico validation with transfer learning between our mouse model and TCGA datasets further demonstrates that many of the site-associated features are detectable even in the context of different primary tumors. Conclusions Determining the distinctive immune-suppressive features in multiple liver and lung TME datasets provides further insight into the tissue specificity of molecular and cellular pathways, suggesting a potential mechanism underlying the discordant clinical responses that are often observed in metastatic diseases.

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

scholarly journals Experimentally Approaching the ICU: Monitoring Outcome-Based Responses in the Two-Hit Mouse Model of Posttraumatic Sepsis

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Susanne Drechsler ◽  
Katrin M. Weixelbaumer ◽  
Heinz Redl ◽  
Martijn van Griensven ◽  
Soheyl Bahrami ◽  
...  
Keyword(s):  
Mouse Model ◽  
Femur Fracture ◽  
Cecal Ligation ◽  
Blood Sampling ◽  
Cecal Ligation And Puncture ◽  
Organ Function ◽  
Daily Monitoring ◽  
Circulating Cells ◽  
Facial Vein ◽  
Insight Into

To simulate and monitor the evolution of posttraumatic sepsis in mice, we combined a two-hit model of trauma/hemorrhage (TH) followed by polymicrobial sepsis with repetitive blood sampling. Anesthetized mice underwent femur fracture/sublethal hemorrhage and cecal ligation and puncture (CLP) 48 h later. To monitor outcome-dependent changes in circulating cells/biomarkers, mice were sampled daily (facial vein) for 7 days and retrospectively divided into either dead (DIE) or surviving (SUR) by post-CLP day 7. Prior to CLP, AST was 3-fold higher in DIE, while all other post-TH changes were similar between groups. There was a significant post-CLP intergroup separation. In SUR, RBC and Hb were lower, platelets and neutrophils higher, and lymphocytes mixed compared to DIE. In DIE, all organ function markers except glucose (decrease) were few folds higher compared to SUR. In summary, the combination of daily monitoring with an adequate two-hit model simulates the ICU setting, allows insight into outcome-based responses, and can identify biomarkers indicative of death in the acute posttraumatic sepsis in mice.

scholarly journals DIPG-68. ALPHA-THALASSEMIA X-LINKED MENTAL RETARDATION PROTEIN (ATRX) LOSS-OF-FUNCTION IN A MOUSE MODEL OF DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii300-iii300
Author(s):  
Chen Shen ◽  
David Picketts ◽  
Oren Becher
Keyword(s):  
Mouse Model ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Tumor Incidence ◽  
Loss Of Function ◽  
Nestin Expression ◽  
Genetically Engineered Mouse Model ◽  
Clinical Cases

Abstract Diffuse Intrinsic Potine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Previous discoveries have revealed that, DIPG harbors distinct genetic alterations, when compared with adult high-grade glioma (HGG) or even with non-DIPG pediatric HGGs. ATRX alteration is found in 9% of clinical cases of DIPG, and significantly overlaps with H3.3K27M mutation and p53 loss, the two most common genetic changes in DIPG, found in 80% and 77% clinical cases, respectively. Here we developed genetically engineered mouse model of brainstem glioma using the RCAS-Tv-a system by targeting PDGF-B overexpression, p53 loss, H3.3K27M mutation and ATRX loss-of function to Nestin-expression brainstem progenitor cells of the neonatal mouse. Specifically, we used Nestin-Tv-a; p53 floxed; ATRX heterozygous female and Nestin-Tv-a; p53 floxed; ATRX floxed male breeders, generated offsprings with ATRX loss of function (n=18), ATRX heterozygous females (n=6), and ATRX WT (n=10). Median survial of the three groups are 65 days, 88 days and 51 days, respectively. Also, ATRX null mice is lower in tumor incidence (44.4%), compared with ATRX WT (80%). We evaluated the pathological features of DIPG with or without ATRX alteration, RNA-seq is performed to identify differentially expressed genes between ATRX WT and loss-of-function. In conclution, this study generated the first genetically modified mouse model studying ATRX loss-of-function in DIPG, and suggested that ATRX loss-of-function in DIPG may slow down tumorigenesis and decrease tumor incidence.

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