Induction of specific locus mutations in mouse spermatogonial stem cells by combined chemical X-ray treatments

Cattanach, B.M.; Peters, Josephine; Rasberry, C.

doi:10.1016/0027-5107(89)90025-0

Cited by 11 publications

(2 citation statements)

References 36 publications

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“…To overcome this limitation, mouse models can be used to investigate the genetic basis of such disorders 7–9. Thus, targeted disruption and transgenic overexpression techniques are used to study the phenotypic effects of known genes, whereas radiation and chemical mutagenesis techniques10 such as N ‐ethyl‐ N ‐nitrosourea (ENU)11 are commonly used to identify novel disease causing genes and pathways with no prior knowledge of genes required. ENU has proved to be very useful in establishing mouse models with dominant, recessive, gain‐ and loss‐of‐function mutations, as well as hypermorphs and hypomorphs12 for many different disorders, including skeletal dysplasias,13, 14 deafness,15 and type 2 diabetes 16, 17.…”

Section: Introductionmentioning

confidence: 99%

A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation

Esapa

Hough

Testori

et al. 2011

Journal of Bone and Mineral Research

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Progeny of mice treated with the mutagen N-ethyl-N-nitrosourea (ENU) revealed a mouse, designated Longpockets (Lpk), with short humeri, abnormal vertebrae, and disorganized growth plates, features consistent with spondyloepiphyseal dysplasia congenita (SEDC). The Lpk phenotype was inherited as an autosomal dominant trait. Lpk/þ mice were viable and fertile and Lpk/Lpk mice died perinatally. Lpk was mapped to chromosome 15 and mutational analysis of likely candidates from the interval revealed a Col2a1 missense Ser1386Pro mutation. Transient transfection of wild-type and Ser1386Pro mutant Col2a1 c-Myc constructs in COS-7 cells and CH8 chondrocytes demonstrated abnormal processing and endoplasmic reticulum retention of the mutant protein. Histology revealed growth plate disorganization in 14-day-old Lpk/þ mice and embryonic cartilage from Lpk/þ and Lpk/Lpk mice had reduced safranin-O and type-II collagen staining in the extracellular matrix. The wild-type and Lpk/þ embryos had vertical columns of proliferating chondrocytes, whereas those in Lpk/Lpk mice were perpendicular to the direction of bone growth. Electron microscopy of cartilage from 18.5 dpc wild-type, Lpk/þ, and Lpk/Lpk embryos revealed fewer and less elaborate collagen fibrils in the mutants, with enlarged vacuoles in the endoplasmic reticulum that contained amorphous inclusions. Micro-computed tomography (CT) scans of 12-week-old Lpk/þ mice revealed them to have decreased bone mineral density, and total bone volume, with erosions and osteophytes at the joints. Thus, an ENU mouse model with a Ser1386Pro mutation of the Col2a1 C-propeptide domain that results in abnormal collagen processing and phenotypic features consistent with SEDC and secondary osteoarthritis has been established. ß

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Section: Introductionmentioning

confidence: 99%

A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation

Esapa

Hough

Testori

et al. 2011

Journal of Bone and Mineral Research

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“…The interpretation is that the cell population is heterogeneous in sensitivity, both to mutagenesis and to cell-killing. As the dose is increased the sensitive cells are preferentially killed, leaving only the mutagenic response of the resistant fraction (Leenhouts & Chadwick 1981;Cattanach 1986). Similar dose-response curves have been obtained with other mammalian species, including laboratory species and various primates, up to about nine species so far (Lyon & Cox 1975;van Buul 1980van Buul , 1983Matsuda et al 1984Matsuda et al , 1985.…”

Section: Radiationmentioning

confidence: 99%

Experimental work on induced mutations

Lyon

1988

Phil. Trans. R. Soc. Lond. B

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The detection of changes in mutation rate in human populations remains extremely difficult. Thus estimation of genetic hazards of mutagens to man depends on extrapolation from experimental systems. Germ cells of animals show complex variations in sensitivity to mutagenic effects. Some agents predominantly affect stem cells or other immature germ cells, whereas others mainly affect later germ cell stages. Dose-response relations also vary both with the agent and with the stage or sex of germ cell treated. In man, in addition to single-gene defects and chromosome anomalies, conditions of complex or uncertain inheritance, such as congenital malformations, are clinically important. Genetic theory leaves unclear whether the incidence of these would be affected by a change in mutation rate. Recent research has shown that in mice the incidence of malformations is increased by exposure of the parents to mutagens, but the effect is small. Chromosomal non-disjunction is also clinically important. Again, recent research shows that its frequency can be changed by mutagens, but the effects vary with germ-cell stage. Thus, further research is needed to elucidate the relative contributions of different environmental mutagens to human genetic disease.

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Quantitative correlation between radiation-induced mutagenesis in endogenous genes and transgenes of mouse spermatogonial stem cells

Martus

Novak

Blecher

et al. 1999

Environ. Mol. Mutagen.

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Induction of specific locus mutations in mouse spermatogonial stem cells by combined chemical X-ray treatments

Cited by 11 publications

References 36 publications

A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation

A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation

Experimental work on induced mutations

Quantitative correlation between radiation-induced mutagenesis in endogenous genes and transgenes of mouse spermatogonial stem cells

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