A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice

Masuya, Hiroshi; Nishida, Keiichiro; Furuichi, Tatsuya; Toki, Hideaki; Nishimura, Gen; Kawabata, Hidehiko; Yokoyama, Haruhiko; Yoshida, Aki; Tominaga, Sayaka; Nagano, Junko; Shimizu, Aya; Wakana, Shigeharu; Gondo, Yoichi; Noda, Tetsuo; Shiroishi, Toshihiko; Ikegawa, Shiro

doi:10.1093/hmg/ddm195

Cited by 59 publications

(46 citation statements)

References 48 publications

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“…We also examined the expression of gdf5. Gdf5 is expressed in the joints of both amniote limbs and zebrafish fin radials and it is required for correct joint formation in mouse limbs Kingsley, 1996, 1999;Francis-West et al, 1999;Settle et al, 2003;Masuya et al, 2007). In contrast, we did not find any expression of gdf5 in lepidotrichia joints.…”

Section: Introductioncontrasting

confidence: 69%

“…GDF5 is required for the formation of at least some tetrapod limb joints Kingsley, 1996, 1999;Francis-West et al, 1999;Settle et al, 2003;Masuya et al, 2007) and consistent with the above-mentioned homology, gdf5 expression can be observed in endoskeleton joints in the fins during zebrafish larval development (Crotwell et al, 2001; Fig. 4G).…”

Section: Developmental Dynamicssupporting

confidence: 63%

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Evx1 is required for joint formation in zebrafish fin dermoskeleton

Schulte

Allen

England

et al. 2011

Developmental Dynamics

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The transcription factor Evx1 is expressed in the joints between individual lepidotrichia (bony ray) segments and at the distal tips of the lepidotrichia in developing zebrafish fins. It is also expressed in the apical growth zone in regenerating fins. However, so far there is no functional evidence that addresses whether Evx1 is required for any aspect of fin development or regeneration. In this study, we use a novel mutation in evx1 to address this. We find that Evx1 is not required for either fin outgrowth or regeneration. All of the fins form normally in evx1 mutants, and there are no significant changes in fin length. In contrast, Evx1 is required for lepidotrichia joint formation during both fin development and regeneration. This is a very specific phenotype as both lepidotrichia hemisegment separations and lepidotrichia bifurcations still form normally in evx1 mutant fins, as do joints in the more proximal endoskeletal radials. Developmental Dynamics 240:1240-1248,

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Section: Introductioncontrasting

confidence: 69%

Section: Developmental Dynamicssupporting

confidence: 63%

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Schulte

Allen

England

et al. 2011

Developmental Dynamics

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“…From this point of view, manipulation of the GDF5/BMPR/Smad/PGC-1a pathway is a plausible strategy to promote the BAT activity required for protection against obesity and a variety of obesity-related metabolic diseases, with a risk of joint and skeletal malformation in childhood. Because GDF5 is initially synthesized as a monomeric proform that undergoes post-translational processing to produce a dimeric mature form for exocytotic release (23), promotion of GDF5 activity would be an alternative approach for the discovery and development of novel strategies beneficial for activating BAT functions to combat against obesity in human beings.…”

Section: Discussionmentioning

confidence: 99%

“…Rgsc451 mice (M100451) were provided by the RIKEN BioResource Center through the National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan (23). The ob/ob mice with the C57BL/6 background were obtained from Japan SLC.…”

Section: Gdf5mentioning

confidence: 99%

Growth Differentiation Factor-5 Promotes Brown Adipogenesis in Systemic Energy Expenditure

et al. 2013

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Although growth differentiation factor-5 (GDF5) has been implicated in skeletal development and joint morphogenesis in mammals, little is known about its functionality in adipogenesis and energy homeostasis. Here, we show a critical role of GDF5 in regulating brown adipogenesis for systemic energy expenditure in mice. GDF5 expression was preferentially upregulated in brown adipose tissues from inborn and acquired obesity mice. Transgenic overexpression of GDF5 in adipose tissues led to a lean phenotype and reduced susceptibility to diet-induced obesity through increased systemic energy expenditure. Overexpression of GDF5 facilitated the development of brown fat-like cells, called brite or beige cells, along with the expression of uncoupling protein-1 in inguinal subcutaneous white adipose tissue. In mutant mice harboring the dominant-negative GDF5, marked impairment in energy expenditure and thermogenesis was seen under obesogenic conditions. Recombinant GDF5 promoted brown adipogenesis through the mothers against decapentaplegic homolog (Smad) and peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) pathways after activation of bone morphogenetic protein receptor (BMPR). These results suggest that brown adipogenesis and energy homeostasis are both positively regulated by the GDF5/BMPR/Smad/PGC-1α signaling pathway in adipose tissues. Modulation of these pathways might be an effective therapeutic strategy for obesity and type 2 diabetes.

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“…A new Gdf5 allele, Gdf5 Rgsc451 , carries an amino acid substitution (W408R) which is a dominant negative form of GDF5 protein. The heterozygous mutant mice exhibit brachypodism and ankylosis, while the homozygous mice suffer from much severer phenotypes associated with early-onset of OA [30]. DISC1 has been reported as a causative gene of human depression and schizophrenia.…”

Section: Enu-induced Mutant Micementioning

confidence: 99%

The Mouse Resources at the RIKEN BioResource Center

et al. 2009

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Abstract:Mice are one of the most important model organisms for studying biological phenomena and diseases processes in life sciences. The biomedical research community has succeeded in launching large scale strategic knockout mouse projects around the world. RIKEN BRC, a comprehensive government funded biological resource center was established in 2001. RIKEN BRC has been acting as the core facility for the mouse resources of the National BioResource Project (NBRP) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan since 2002. RIKEN BRC is a founding member of the Federation of International Mouse Resources (FIMRe) together with the Jackson Laboratory, the European Mouse Mutant Archive, and other centers, and has participated in the International Mouse Strain Resource (IMSR) to distribute mouse strains worldwide. With the support of the scientific community, RIKEN BRC has collected over 3,800 strains including inbred, transgenic, knockout, wild-derived, and ENU-induced mutant strains. Excellent mouse models for human diseases and gene functions from academic organizations and private companies are distributed through RIKEN BRC. To meet research and social needs, our mice will be rederived to a specific pathogen-free state, strictly monitored for their health, and accurately tested for their genetic modifications and backgrounds. Users can easily access our mouse resources through the internet and obtain the mouse strains for a minimal fee. Cryopreservation of embryos and sperm is used for efficient preservation of the increasing number of mouse resources. RIKEN BRC collaborates with FIMRe members to support Japanese scientists in the use of valuable mouse resources from around the world.

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A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice

Cited by 59 publications

References 48 publications

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Evx1 is required for joint formation in zebrafish fin dermoskeleton

Growth Differentiation Factor-5 Promotes Brown Adipogenesis in Systemic Energy Expenditure

The Mouse Resources at the RIKEN BioResource Center

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