Usefulness of ICR mice as genetic resources

ICR(Yok:ICR)mice were introduced into the National Instltute of Infectious Diseases in 1965,and have been bred and produced there.Two inbred mutant mouse strains,MPS and ICGN,were created using(originated from)Yok:ICR mice in 1986.The MPS and ICGN mouse strains have served as the animal disease models of mycoplasma infectious disease and congenital nephritic syndrome,respectively. Genetic variations were detected by the genetic monitoring of Yok:ICR mice using biochemical markers.However, no difference was detected in gene expression profiles between the MPS and ICGN mouse strains.ICR mice may harbor genes that are spontaneously mutated,thereby allowing the creation of new pathological models through the segregation and/or selection(screening)of mutant genes

Study on the usefulness of Meg1Crb10 transgenic mouse as aType2 diabetes mellitus model animal. -Analysis of blood plasma component and expression of genes related to onset of diabetes -

Meg1/Grb10遺伝子導入マウス（Meg1マウス）はインスリンのシグナル伝達阻害による高インスリン血症を呈することから2型糖尿病モデルと考えられている。Meg1マウスは肥満を伴なわずに高血糖を発症するが､脂肪･カロリーの過剰摂取によっても糖尿病の発症が著しく増加する｡本研究はMeg1マウスの2型糖尿病モデルとしての有用性を検討するために､Meg1マウスと対照マウスを高脂肪･高カロリー飼料（HFD）及び対照飼料（NFD）で飼育した時の血漿アディポネクチン量とBMI値を比較するとともに糖尿病関連遺伝子の発現量について他の糖尿病モデルマウスと比較検討した。血漿アディポネクチン量はMeg1マウスのHFDが最も高く､対照マウスのNFDが最も低い値を示した。一方､BMI値は対照マウスのHFDが最も高い値を示し､血漿アディポネクチン量とBMI値は逆相関が認められ､ヒト2型糖尿病と類似することが認められた。また､Grb10､Glut4遺伝子の発現量はMeg1マウスと他の糖尿病モデルマウスでは異なる値を示し､Meg1マウスでのGrb10遺伝子の発現量は高く､Glut4遺伝子の発現量は低かった。以上のことから､Meg1マウスには他の糖尿病モデルと異なる発症機構の存在が示唆され､Meg1マウスは2型糖尿病モデルとしての有用性が考えられた

Analysis of plasma components related to onset of diabetes in Meg1/Grb10 transgenic mice

2型糖尿病は肥満から糖尿病を発症すると考えられており､Meg1マウスは通常飼料では肥満を伴わないが､高カロリー飼料を摂取することによりグルコース代謝の異常によって糖尿病を発症する｡Meg1/Grb10遺伝子導入マウス(Meg1マウス)はインスリンのシグナル伝達阻害によるインスリン抵抗性を呈することから2型糖尿病モデルと考えられている｡本研究は､糖尿病発症機序の解明を目的として､Meg1/Grb10遺伝子導入マウス(Meg1マウス､TG+)とコントロールのマウス(Meg1マウスの親系統であるC57BL/6N;TG-)の雄を用いて高カロリー･高脂肪飼料を給餌した場合のグルコース代謝におけるシグナル伝達阻害の影響について血漿成分の面から検討した｡その結果､血漿中のIGF､BUN値はいずれもTG+がTG-より有意に低く､一方､中性脂肪量はTG+ がTG-より有意に高かった｡Meglマウスで認められたインスリン値の増加とIGF-1値の減少はインスリン伝達経路においてGrb10がインスリン受容体への結合を阻害していることの証明といえる｡Meg1マウスにおける高インスリン血症はインスリン抵抗性の結果と考えられる

Effect of High-Fat and High-Calorie Diets on the Onset of Diabetes in Meg1/Grb10 Transgenic Mice

Meg1/Grb10遺伝子導入マウスはインスリンのシグナル伝達阻害による高インスリン血症を呈することから､II型糖尿病モデルと考えられている｡そこで､本モデルマウスを用いてII型糖尿病発症に及ぼす飼料の影響について検討した結果､ヒトII型糖尿病モデルとして有用性を確認することが出来た

Adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes: a new model for dilated cardiomyopathy

Sugar chain abnormalities in glycolipids and glycoproteins are associated with various diseases. Here, we report an adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes. The transgenic hearts at the end-stage, at around 7 months old, were enlarged, with enlarged cavities and thin, low-tensile walls, typical of dilated cardiomyopathy. Although no apparent change was found in heart gangliosides, glycosylation of heart proteins was altered. Interestingly, sugar moieties not directly related to the ST3Gal-II catalytic reaction were also changed. Significant increases in calreticulin and calnexin were observed in hearts of the transgenic mice. These results suggest that expression of ST3Gal-II transgenes induces abnormal protein glycosylation, which disorganizes the endoplasmic/sarcoplasmic reticulum quality control system and elevates the calreticulin/calnexin level, resulting in suppression of cardiac function. The transgenic mice showed 100% incidence of adult onset cardiac dilatation, suggesting great potential as a new model for dilated cardiomyopathy

A Potent Inhibitor of SIK2, 3, 3′, 7-Trihydroxy-4′-Methoxyflavon (4′-O-Methylfisetin), Promotes Melanogenesis in B16F10 Melanoma Cells

Flavonoids, which are plant polyphenols, are now widely used in supplements and cosmetics. Here, we report that 4′-methylflavonoids are potent inducers of melanogenesis in B16F10 melanoma cells and in mice. We recently identified salt inducible kinase 2 (SIK2) as an inhibitor of melanogenesis via the suppression of the cAMP-response element binding protein (CREB)-specific coactivator 1 (TORC1). Using an in vitro kinase assay targeting SIK2, we identified fisetin as a candidate inhibitor, possibly being capable of promoting melanogenesis. However, fisetin neither inhibited the CREB-inhibitory activity of SIK2 nor promoted melanogenesis in B16F10 melanoma cells. Conversely, mono-methyl-flavonoids, such as diosmetin (4′-O-metlylluteolin), efficiently inhibited SIK2 and promoted melanogenesis in this cell line. The cAMP-CREB system is impaired in Ay/a mice and these mice have yellow hair as a result of pheomelanogenesis, while Sik2+/−; Ay/a mice also have yellow hair, but activate eumelanogenesis when they are exposed to CREB stimulators. Feeding Sik2+/−; Ay/a mice with diets supplemented with fisetin resulted in their hair color changing to brown, and metabolite analysis suggested the presence of mono-methylfisetin in their feces. Thus, we decided to synthesize 4′-O-methylfisetin (4′MF) and found that 4′MF strongly induced melanogenesis in B16F10 melanoma cells, which was accompanied by the nuclear translocation of TORC1, and the 4′-O-methylfisetin-induced melanogenic programs were inhibited by the overexpression of dominant negative TORC1. In conclusion, compounds that modulate SIK2 cascades are helpful to regulate melanogenesis via TORC1 without affecting cAMP levels, and the combined analysis of Sik2+/− mice and metabolites from these mice is an effective strategy to identify beneficial compounds to regulate CREB activity in vivo