Mouse ENU Mutagenesis

Justice, Monica J.; Noveroske, Janice K.; Weber, John; Zheng, Binhai; Bradley, Allan

doi:10.1093/hmg/8.10.1955

Cited by 406 publications

(262 citation statements)

References 64 publications

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“…However, a significant percentage of mutations (6/31 = 19%) were single-exon deletions, which were most likely caused by point mutations at the genomic level at sites that are relevant for pre-mRNA splicing. This observation is in line with other data [13][14][15] and opened up the possibility of focusing a screening strategy on this particular type of mutation. Since the exon structure of genes is usually known, deletions of exons at the cDNA level can be detected specifically using exon-skipping primers (Fig.…”

Section: Resultssupporting

confidence: 89%

Mouse splice mutant generation from ENU-treated ES cells—A gene-driven approach

2005

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Mutant mice are important for elucidating mammalian gene functions and for modeling human disease phenotypes. In recent years, chemical mutagenesis has become an increasingly popular method to disrupt gene functions due to its high efficiency of inducing mutations throughout the genome. Mutagenesis of embryonic stem (ES) cells offers the possibility of gene-driven approaches, which, however, require efficient mutation detection procedures to screen archives of mutated samples for lesions in particular genes. We have developed an approach that focuses on the detection of splice mutations in highly pooled cDNA samples using exon-skipping PCR primers. As a proof of concept, splice mutants for the Kit gene were isolated from a library comprising approximately 40,000 ES cell clones treated with N-ethyl-Nnitrosourea followed by transmission through the mouse germ-line. The approach will be useful for the production of mouse models for human disease-related splice mutations and as a general gene disruption strategy. D

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Section: Resultssupporting

confidence: 89%

Mouse splice mutant generation from ENU-treated ES cells—A gene-driven approach

2005

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“…8 One such carcinogen is ENU, a DNA ethylating agent that induces widespread DNA damage, resulting in singlenucleotide mutations, most commonly T:A to A:T transversions and T:A to C:G transitions. 9 Rats in particular have been treated with ENU either during embryonic development or postnatally to induce gliomagenesis, and the resulting gliomas were either characterized within the intact brain or harvested to establish adherent cell lines cultured in vitro in serum-containing media.…”

Section: Modeling Gliomas Using Enumentioning

confidence: 99%

BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea–Induced Gliomagenesis

McNeill

Irvin

Miller

2016

The American Journal of Pathology

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In this issue of the American Journal of Pathology, Wang et al 1 identified recurrent Braf mutations in N-ethyl-Nnitrosourea (ENU)einduced rat gliomas by DNA sequencing. Their results provide a platform for preclinical development of novel targeted therapies for BRAF-mutant gliomas. Precision oncology promises to revolutionize cancer therapy by stratifying tumors on the basis of their molecular characteristics and using rationally designed treatments in molecularly defined patient populations. 2 Although the field of oncology is transitioning into the precision medicine era, conventional diagnostics, based on tissue type, tumor pathology, and patient demographics, remain essential to quality care. One natural pathological division for gliomas, the most common primary brain tumors in humans, is based on their invasion, with nondiffuse gliomas forming well-circumscribed tumors and diffuse gliomas invading the normal brain. 3 Within these two broad diagnostic categories, gliomas are further subdivided on the basis of patient demographics into pediatric and adult diseases and further into specific diagnostic entities based on their histological appearance.

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“…ENU can cause not only complete loss-of-function mutations, similar to conventional gene-targeting techniques, but also partial loss-of-function, dominant-negative, and gain-of-function mutations. Over the past decade, large-scale mutagenesis projects involving the use of ENU to generate novel mouse mutants have been undertaken worldwide with the goal of modeling human diseases and describing the function of each mammalian gene (reviewed in [6,8]). …”

Section: N-ethyl-n-nitrosourea (Enu) Is a Chemical Mutagenmentioning

confidence: 99%

ENU Mutagenesis Screening for Dominant Behavioral Mutations Based on Normal Control Data Obtained in Home-Cage Activity, Open-Field, and Passive Avoidance Tests

et al. 2010

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Abstract:To establish the cutoff values for screening ENU-induced behavioral mutations, normal variations in mouse behavioral data were examined in home-cage activity (HA), openfield (OF), and passive-avoidance (PA) tests. We defined the normal range as one that included more than 95% of the normal control values. The cutoffs were defined to identify outliers yielding values that deviated from the normal by less than 5% for C57BL/6J, DBA/2J, DBF 1 , and N 2 (DXDB) progenies. Cutoff values for G1-phenodeviant (DBF 1 ) identification were defined based on values over ±3.0 SD from the mean of DBF 1 for all parameters assessed in the HA and OF tests. For the PA test, the cutoff values were defined based on whether the mice met the learning criterion during the 2nd (at a shock intensity of 0.3 mA) or the 3rd (at a shock intensity of 0.15 mA) retention test. For several parameters, the lower outliers were undetectable as the calculated cutoffs were negative values. Based on the cutoff criteria, we identified 275 behavioral phenodeviants among 2,646 G1 progeny. Of these, 64 were crossed with wild-type DBA/2J individuals, and the phenotype transmission was examined in the G2 progeny using the cutoffs defined for N 2 mice. In the G2 mice, we identified 15 novel dominant mutants exhibiting behavioral abnormalities, including hyperactivity in the HA or OF tests, hypoactivity in the OF test, and PA deficits. Genetic and detailed behavioral analysis of these ENU-induced mutants will provide novel insights into the molecular mechanisms underlying behavior.

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Mouse ENU Mutagenesis

Cited by 406 publications

References 64 publications

Mouse splice mutant generation from ENU-treated ES cells—A gene-driven approach

Mouse splice mutant generation from ENU-treated ES cells—A gene-driven approach

BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea–Induced Gliomagenesis

ENU Mutagenesis Screening for Dominant Behavioral Mutations Based on Normal Control Data Obtained in Home-Cage Activity, Open-Field, and Passive Avoidance Tests

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