The mammalian gene function resource: the international knockout mouse consortium

Bradley, Allan; Anastassiadis, Konstantinos; Ayadi, A.; Battey, James F.; Bell, Cindy; Birling, Marie‐Christine; Bottomley, Joanna; Brown, Steve; Bürger, Antje; Bult, Carol J.; Bushell, Wendy; Collins, Francis S.; Desaintes, Christian; Doe, Brendan; Economides, Aris N.; Eppig, Janan T.; Finnell, Richard H.; Fletcher, Colin; Fray, Martin; Frendewey, David; Friedel, Roland H.; Grosveld, Frank; Hansen, Jens; Hérault, Yann; Hicks, Geoffrey; Hörlein, Andreas; Houghton, Richard; Angelis, Martin Hrabé de; Huylebroeck, Danny; Iyer, Vivek; Jong, Pieter J. de; Kadin, James A.; Kaloff, Cornelia; Kennedy, Karen; Koutsourakis, Manousos; Lloyd, Kevin C K; Marschall, Susan; Mason, Jeremy; McKerlie, Colin; McLeod, Michael P.; Melchner, Harald von; Moore, Mark; Mujica, Alejandro O.; Nagy, András; Nefedov, Mikhail; Nutter, Lauryl M. J.; Pavlovic, Guillaume; Peterson, Jane; Pollock, Jonathan; Ramirez-Solis, Ramiro; Rancourt, Derrick E.; Raspa, Marcello; Remacle, Jacques; Ringwald, Martin; Rosen, Barry; Rosenthal, Nadia; Rossant, Janet; Noppinger, Patricia Ruiz; Ryder, Edward; Schick, Joel; Schnütgen, Frank; Schofield, Paul N.; Seisenberger, Claudia; Selloum, Mohammed; Simpson, Elizabeth M.; Skarnes, William C.; Smedley, Damian; Stanford, William L.; Stewart, A. Francis; Stone, Kevin R.; Swan, Kate; Tadepally, Hamsa D.; Teboul, Lydia; Tocchini‐Valentini, Glauco P.; Valenzuela, David M.; West, Anthony P.; Yamamura, Ken‐ichi; Yoshinaga, Yuko; Wurst, Wolfgang

doi:10.1007/s00335-012-9422-2

Cited by 287 publications

(228 citation statements)

References 10 publications

(10 reference statements)

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“…Given the extraordinary increase in targeted mouse model resources 4 and the availability of 'speed congenic' breeding methodology 23 , it will probably soon be possible to promptly generate, within four or five generations of breeding, a wildbackcrossed mutant mouse model for any gene in the mouse genome. Notably, during the backcrossing procedure, we observed (data not shown) that within three generations of backcrossing the wild-backcrossed mouse model exhibits behavioural traits strongly resembling those of the wild mice, including all the traits that were present in wild mice but absent in laboratory mice.…”

Section: Discussionmentioning

confidence: 99%

“…Targeted gene mutation (knockout/knockin) in cultured embryonic stem cells derived from inbred laboratory mouse strains, usually in the 129/Sv genetic background and later backcrossed to C57BL/6 mice, is widely considered as the 'gold standard' approach to evaluate gene function in mammals and to provide preclinical models of diseases 1,2 . This strategy has already resulted in the production of thousands of mutant mouse models and numerous gene-phenotype associations 3,4 (ftp://ftp.informatics.jax.org/pub/reports/). However, despite tremendous multidisciplinary efforts, the basic mechanisms underlying complex behaviours are still poorly understood, and the molecular and neuronal bases of social behaviours and their related disorders have remained elusive.…”

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confidence: 99%

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Mapping ecologically relevant social behaviours by gene knockout in wild mice

et al. 2014

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The laboratory mouse serves as an important model system for studying gene, brain and behavioural interactions. Powerful methods of gene targeting have helped to decipher gene-function associations in human diseases. Yet, the laboratory mouse, obtained after decades of human-driven artificial selection, inbreeding, and adaptation to captivity, is of limited use for the study of fitness-driven behavioural responses that characterize the ancestral wild house mouse. Here, we demonstrate that the backcrossing of wild mice with knockout mutant laboratory mice retrieves behavioural traits exhibited exclusively by the wild house mouse, thereby unmasking gene functions inaccessible in the domesticated mutant model. Furthermore, we show that domestication had a much greater impact on females than on males, erasing many behavioural traits of the ancestral wild female. Hence, compared with laboratory mice, wild-derived mutant mice constitute an improved model system to gain insights into neuronal mechanisms underlying normal and pathological sexually dimorphic social behaviours.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mapping ecologically relevant social behaviours by gene knockout in wild mice

et al. 2014

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“…The MGI allele name is OMP tm17Mom . ES cell clone EPD0413_2_B07 was generated by the trans‐NIH Knockout Mouse Project (KOMP) (Bradley et al ., 2012) as IKMC project 26474 with targeting vector DPGS00176_A_D03, and obtained from the KOMP Repository at UC Davis. This ES cell clone was derived from the parental ES cell line JM8A3.N1, and is of the type reporter‐tagged deletion allele (with selection cassette) without conditional potential.…”

Section: Methodsmentioning

confidence: 99%

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

Köentgen¹,

Lin

Κατίδου

et al. 2016

Genesis

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SummaryGene targeting in embryonic stem (ES) cells remains best practice for introducing complex mutations into the mouse germline. One aspect in this multistep process that has not been streamlined with regard to the logistics and ethics of mouse breeding is the efficiency of germline transmission: the transmission of the ES cell‐derived genome through the germline of chimeras to their offspring. A method whereby male chimeras transmit exclusively the genome of the injected ES cells to their offspring has been developed. The new technology, referred to as goGermline, entails injecting ES cells into blastocysts produced by superovulated homozygous Tsc22d3 floxed females mated with homozygous ROSA26‐Cre males. This cross produces males that are sterile due to a complete cell‐autonomous defect in spermatogenesis. The resulting male chimeras can be sterile but when fertile, they transmit the ES cell‐derived genome to 100% of their offspring. The method was validated extensively and in two laboratories for gene‐targeted ES clones that were derived from the commonly used parental ES cell lines Bruce4, E14, and JM8A3. The complete elimination of the collateral birth of undesired, non‐ES cell‐derived offspring in goGermline technology fulfills the reduction imperative of the 3R principle of humane experimental technique with animals. genesis 54:326–333, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.

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“…As part of a long-term effort to fully ascribe function to the entire genome, the International Knockout Mouse Consortium (IKMC; www.mousephenotype.org) (Bradley et al 2012) was initiated in 2007 to create a resource of gene-specific knockout embryonic stem (ES) cells for all protein-coding genes in the mouse genome. To date, this global cooperative project has produced sets of targeted and/or gene-trapped cell lines for ∼17,000 unique genes, primarily using ES cells derived from the C57BL/6N inbred mouse strain.…”

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confidence: 99%

A lacZ reporter gene expression atlas for 313 adult KOMP mutant mouse lines

et al. 2015

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Expression of the bacterial beta-galactosidase reporter gene (lacZ) in the vector used for the Knockout Mouse Project (KOMP) is driven by the endogenous promoter of the target gene. In tissues from KOMP mice, histochemical staining for LacZ enzyme activity can be used to determine gene expression patterns. With this technique, we have produced a comprehensive resource of gene expression using both whole mount (WM) and frozen section (FS) LacZ staining in 313 unique KOMP mutant mouse lines. Of these, ∼80% of mutants showed specific staining in one or more tissues, while ∼20% showed no specific staining, ∼13% had staining in only one tissue, and ∼25% had staining in >6 tissues. The highest frequency of specific staining occurred in the brain (∼50%), male gonads (42%), and kidney (39%). The WM method was useful for rapidly identifying whole organ and some substructure staining, while the FS method often revealed substructure and cellular staining specificity. Both staining methods had >90% repeatability in biological replicates. Nonspecific LacZ staining occurs in some tissues due to the presence of bacteria or endogenous enzyme activity. However, this can be effectively distinguished from reporter gene activity by the combination of the WM and FS methods. After careful annotation, LacZ staining patterns in a high percentage of mutants revealed a unique structure-function not previously reported for many of these genes. The validation of methods for LacZ staining, annotation, and expression analysis reported here provides unique insights into the function of genes for which little is currently known.[Supplemental material is available for this article.]

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The mammalian gene function resource: the international knockout mouse consortium

Cited by 287 publications

References 10 publications

Mapping ecologically relevant social behaviours by gene knockout in wild mice

Mapping ecologically relevant social behaviours by gene knockout in wild mice

Exclusive transmission of the embryonic stem cell‐derived genome through the mouse germline

A lacZ reporter gene expression atlas for 313 adult KOMP mutant mouse lines

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