Mouse rump-white mutation associated with an inversion of Chromosome 5

Stephenson, Dennis A.; Lee, K.-H.; Nagle, Deborah L.; Yen, Chao-Huang; Morrow, Arlene D.; Miller, Darla R.; Chapman, Verne M.; Bućan, Maja

doi:10.1007/bf00356552

Cited by 25 publications

(13 citation statements)

References 41 publications

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“…Many extant "classical" chromosomal deletions and inversions have been actively maintained or cryopreserved and are listed in the International Mouse Strain Resources database of the Jackson Laboratory and the Medical Research Council Mammalian Genetics Unit (www.jax.org/pub-cg/imrlist) or in the Mutant Mouse database of the Oak Ridge National Laboratory (www.bio.org.gov/htmouse). Currently, other research groups and mutagenesis centers are using some existing deletions to identify new region-specific mutations (57). The re- a Estimates of mouse numbers that must be produced and screened to examine mice in dominant and recessive screens are shown.…”

Section: Chromosome Engineering and Region-specific Screensmentioning

confidence: 99%

N -Ethyl- N -Nitrosourea Mutagenesis: Boarding the Mouse Mutant Express

Cordes

2005

Microbiol Mol Biol Rev

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In the mouse, random mutagenesis with N-ethyl-N-nitrosourea (ENU) has been used since the 1970s in forward mutagenesis screens. However, only in the last decade has ENU mutagenesis been harnessed to generate a myriad of new mouse mutations in large-scale genetic screens and focused, smaller efforts. The development of additional genetic tools, such as balancer chromosomes, refinements in genetic mapping strategies, and evolution of specialized assays, has allowed these screens to achieve new levels of sophistication. The impressive productivity of these screens has led to a deluge of mouse mutants that wait to be harnessed. Here the basic large- and small-scale strategies are described, as are the basics of screen design. Finally, and importantly, this review describes the mechanisms by which such mutants may be accessed now and in the future. Thus, this review should serve both as an overview of the power of forward mutagenesis in the mouse and as a resource for those interested in developing their own screens, adding onto existing efforts, or obtaining specific mouse mutants that have already been generated

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Section: Chromosome Engineering and Region-specific Screensmentioning

confidence: 99%

N -Ethyl- N -Nitrosourea Mutagenesis: Boarding the Mouse Mutant Express

Cordes

2005

Microbiol Mol Biol Rev

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“…Rw is a radiation-induced mutation causing depigmentation of the posterior and ventral abdomen in heterozygotes and embryonic lethality in homozygotes (Stephenson et al 1994). Recombination in heterozygotes is effectively suppressed throughout the inversion region by elimination of nonviable recombinants, and thus, it serves as a balancer chromosome.…”

mentioning

confidence: 99%

Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations

Wilson

Ching²,

Farias³

et al. 2005

Genome Res.

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A region-specific ENU mutagenesis screen was conducted to elucidate the functional content of proximal mouse Chr 5. We used the visibly marked, recessive, lethal inversion Rump White (Rw) as a balancer in a three-generation breeding scheme to identify recessive mutations within the ∼50 megabases spanned by Rw. A total of 1003 pedigrees were produced, representing the largest inversion screen performed in mice. Test-class animals, homozygous for the ENU-mutagenized proximal Chr 5 and visibly distinguishable from nonhomozygous littermates, were screened for fertility, hearing, vestibular function, DNA repair, behavior, and dysmorphology. Lethals were identifiable by failure to derive test-class animals within a pedigree. Embryonic lethal mutations (total of 34) were overwhelmingly the largest class of mutants recovered. We characterized them with respect to the time of embryonic death, revealing that most act at midgestation (8.5-10.5) or sooner. To position the mutations within the Rw region and to guide allelism tests, we performed complementation analyses with a set of new and existing chromosomal deletions, as well as standard recombinational mapping on a subset of the mutations. By pooling the data from this and other region-specific mutagenesis projects, we calculate that the mouse genome contains ∼3479-4825 embryonic lethal genes, or about 13.7%-19% of all genes.

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“…Specifically, gene duplication and splice mutations in W are responsible for the white coat color in Large White pigs, whereas an inversion mutation in W presents the Rump White color pattern in mice (Stephenson et al, 1994;Marklund et al, 1998). Similarly, piebaldism, a rare human autosomal dominant disorder of melanocyte development, has been traced to a number of point, deletion, splice, and insertion mutations in the W locus (Richards et al, 2001).…”

mentioning

confidence: 99%

Hair Depigmentation Is a Biological Readout for Pharmacological Inhibition of KIT in Mice and Humans

Moss¹,

Toner²,

Cherrington³

et al. 2003

J Pharmacol Exp Ther

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Deregulated activation of the KIT receptor tyrosine kinase has been implicated in several human cancers and in inflammation, making it an attractive target for therapeutic intervention. Conversely, deficiencies in KIT signaling have been implicated in human and animal hair pigmentation disorders, reflecting a role for KIT in the development and function of melanocytes. The goal of this study was to explore the potential utility of hair depigmentation as a biological readout for systemic inhibition of KIT by SU11248 5-, an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptors, vascular endothelial growth factor receptors, KIT, and FLT3. Oral SU11248 treatment induced dose-dependent depigmentation of newly regrown hair in depilated C57BL/6 mice. Similar effects were seen after administration of a KIT-neutralizing antibody. SU11248-induced hair depigmentation was reversible with cessation of treatment. Histological and immunohistochemical evaluation of mouse skin samples supported these observations and revealed that SU11248 has no effect on levels of KIT-positive melanocytes associated with hair follicles, indicating that the inhibitory effect is at the level of melanocyte function rather than their development/survival. Similar hair depigmentation has been noted in several cancer patients receiving SU11248 in phase I trials. Strikingly, patient scalp hair exhibits bands of depigmentation and pigmentation that correspond, respectively, to periods of treatment and dosing rest periods. These data demonstrate that hair pigmentation can serve as a dose-dependent, dynamic, biological readout for KIT inhibition in mice, and, apparently, in humans.

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Mouse rump-white mutation associated with an inversion of Chromosome 5

Cited by 25 publications

References 41 publications

N -Ethyl- N -Nitrosourea Mutagenesis: Boarding the Mouse Mutant Express

N -Ethyl- N -Nitrosourea Mutagenesis: Boarding the Mouse Mutant Express

Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations

Hair Depigmentation Is a Biological Readout for Pharmacological Inhibition of KIT in Mice and Humans

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