Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function

Bassett, J. H. Duncan; Logan, John G.; Boyde, A.; Cheung, Moira; Evans, Holly; Sun, Xiaoyang; Xu, Sai; Murata, Yoshiharu; Williams, Graham R.

doi:10.1210/en.2011-1814

Cited by 21 publications

(25 citation statements)

References 45 publications

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“…In mice, two splice variants of Rcan2 that display distinct tissue-specific expression patterns have been identified (Mizuno et al, 2004): Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is also expressed in other tissues, such as the heart and skeletal muscle. Recently, it was reported that loss of Rcan2 function in mice did not affect their linear growth (Bassett et al, 2012), but significantly ameliorated age-and dietinduced obesity by causing a reduction in food intake (Sun et al, 2011). Using double-mutant (Lep ob/ob Rcan2 −/− ) mice, we demonstrated that Rcan2 and leptin regulate body weight through different pathways.…”

Section: Introductionmentioning

confidence: 87%

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

Zhao

Gong

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the development of age-and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone (T3)-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kb1 signaling pathway. Intriguingly, both Rcan2 −/− and Rps6kb1 −/− mutations were reported to result in lean phenotypes in mice. In this study we compared the effects of these two mutations on growth and body weight in C57BL/6J mice. We observed reduced body weight and lower fat mass in both Rcan2 −/− and Rps6kb1 −/− mice compared to the wild-type mice, and we reported other differences unique to either the Rcan2 −/− or Rps6kb1 −/− mice. Firstly, loss of Rcan2 does not directly alter body length; however, Rcan2 −/− mice exhibit reduced food intake. In contrast, Rps6kb1 −/− mice exhibit abnormal embryonic development, which leads to smaller body size and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2 −/− mice weigh significantly more than Rps6kb1 −/− mice, but both Rcan2 −/− and Rps6kb1 −/− mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2 −/− mice gain body weight and fat mass at slower rates than Rps6kb1 −/− mice. Finally, using the double-knockout mice (Rcan2 −/− Rps6kb1 −/− ), we demonstrate that concurrent loss of Rcan2 and Rps6kb1 has an additive effect on body weight reduction in C57BL/6J mice. Our data suggest that Rcan2 and Rps6kb1 mutations both affect growth and body weight of mice, though likely through different mechanisms.

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Section: Introductionmentioning

confidence: 87%

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

Zhao

Gong

et al. 2016

J. Zhejiang Univ. Sci. B

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“…Detailed characterization of the adult skeleton in Thra1 PV /+ mice was performed in 14-week-old female mice after cessation of growth, and in fully mature 20-week-old female mice that had been treated with vehicle or T 4 from weaning at 4 weeks of age until death. All mice were given ip injections of calcein (10 mg/kg in 100 μL PBS) 14 and 7 days before tissue collection (29). …”

Section: Methodsmentioning

confidence: 99%

“…Sections (5 μm) were stained with alcian blue and van Gieson (29, 33). Measurements from at least 4 separate positions across the growth plate were obtained to calculate the mean height using a Leica DM LB2 microscope and DFC320 digital camera (Leica Microsystems).…”

Section: Methodsmentioning

confidence: 99%

Thyroid Hormone Receptor α Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice

et al. 2014

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A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1PV/+ mice express a similar potent dominant-negative mutant TRα1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1PV/+ mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1PV/+ mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRα1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.

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“…19, 2017; Mammalian knockouts for giantin (rat (Katayama et al, 2011) and mouse (Lan et al, 2016)) exhibit defects in extracellular matrix secretion and assembly, cartilage and bone formation, and have syndromic cleft palate. RCAN2 KO mice are viable but show selective defects in osteoblast function (Bassett et al, 2012), in impaired intramembranous ossification, and in cortical bone formation.…”

Section: Cc-by-nc-nd 40 International License Not Peer-reviewed) Ismentioning

confidence: 99%

Regulator of calcineurin-2 is a centriolar protein with a role in cilia length control

Stevenson

Bergen

et al. 2017

Preprint

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Almost every cell in the human body extends a primary cilium. Defective cilia function leads to a set of disorders known as ciliopathies characterised by debilitating developmental defects affecting many tissues. Here we report a new role for regulator of calcineurin 2, RCAN2 in primary cilia function. It localises to centrioles and cilia and is required to maintain normal cilia length. RCAN2 was identified as the most strongly upregulated gene from a comparative RNAseq analysis of cells in which expression of the Golgi matrix protein giantin had been abolished by gene editing. In contrast to previous work where we showed that depletion of giantin by RNAi results in defects in ciliogenesis and in cilia length control, giantin knockout cells generate normal cilia on serum withdrawal.Furthermore, giantin knockout zebrafish show increased expression of RCAN2. Importantly, suppression of RCAN2 expression in giantin knockout cells results in the same defects in cilia length control seen on RNAi of giantin itself. Together these data define RCAN2 as a regulator of cilia function that can compensate for loss of giantin function.

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Mice Lacking the Calcineurin Inhibitor Rcan2 Have an Isolated Defect of Osteoblast Function

Cited by 21 publications

References 45 publications

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

Thyroid Hormone Receptor α Mutation Causes a Severe and Thyroxine-Resistant Skeletal Dysplasia in Female Mice

Regulator of calcineurin-2 is a centriolar protein with a role in cilia length control

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