Multiple physiological roles of cytosolic 3,5,3'-triiodothyronine binding protein (CTBP)

先前，我们在大鼠细胞质中鉴定了nadph依赖的胞质T3结合蛋白（CTBP）。CTBP与m-crystallin （CRYM）相同。最近，在非综合征性遗传性耳聋患者中发现了CRYM突变。虽然已经确定CRYM在体外保存和转运T3到细胞核中起关键作用，并对听力能力有临床影响，但CRYM在体内的确切功能仍有待阐明。为了进一步研究CRYM基因产物的体内功能，我们培养了靶向破坏CRYM基因的小鼠，从而使CRYM的产生消失。CRYM敲除会使脑、肾、心和肝细胞质中nadph依赖的T3结合活性丧失。在甲状腺功能正常状态下，尽管生长正常，心率和听力正常，但敲除可显著抑制血清T3和T4浓度。该基因的破坏不会改变脑垂体中TSHb mRNA的表达，也不会改变肝脏或肾脏中谷胱甘肽S转移酶α 2和去碘酶1 mRNA的表达。经静脉注射放射性标记T3后，标记T3迅速进入并从crym敲除小鼠的组织中逸出。这些数据表明，由于T3的快速转换，CRYM基因的破坏会降低组织和血清中的T3浓度，而不会改变体内外周T3的作用。

Previously, we identified NADPH-dependent cytosolic T3 binding protein (CTBP) in rat cytosol. CTBP is identical to m-crystallin (CRYM). Recently, CRYM mutations were found in patients with non-syndromic hereditary deafness. Although it has been established that CRYM plays pivotal roles in reserving and transporting T3 into the nuclei in vitro and has a clinical impact on hearing ability, the precise functions of CRYM remain to be elucidated in vivo.To further investigate the in vivo functions of CRYM gene products, we have generated mice with targeted disruption of the CRYM gene, which abrogates the production of CRYM. CRYM knockout loses the NADPH-dependent T3 binding activity in the cytosol of the brain, kidney, heart, and liver. At the euthyroid state, knockout significantly suppresses the serum concentration of T3 and T4 despite normal growth, heart rate and hearing ability. The disruption of the gene does not alter the expression of TSHb mRNA in the pituitary gland or glutathione S transferase alpha 2 and deiodinase 1 mRNAs in either the liver or kidney. When radiolabeled T3 is injected intravenously, labeled T3 rapidly enters into then escapes from the tissues in CRYM-knockout mice. These data suggest that because of rapid T3 turnover, disruption of the CRYM gene decreases T3 concentrations in tissues and serum without alteration of peripheral T3 action in vivo.