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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >An agouti mutation lacking the basic domain induces yellow pigmentation but not obesity in transgenic mice
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An agouti mutation lacking the basic domain induces yellow pigmentation but not obesity in transgenic mice

机译：缺乏基本结构域的刺豚鼠突变在转基因小鼠中诱导黄色色素沉着而不引起肥胖

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摘要

Chronic antagonism of melanocortin recep- tors by the paracrine-acting agouti gene product induces both yellow fur and a maturity-onset obesity syndrome in mice that ubiquitously express wild-type agouti. Functional analysis of agouti mutations in transgenic mice indicate that the cysteine- rich C terminus, signal peptide, and glycosylation site are required for agouti activity in vivo. In contrast, no biological activity has been ascribed to the conserved basic domain. To examine the functional significance of the agouti basic do- main, the entire 29-aa region was deleted from the agouti cDNA, and the resulting mutation (agouti#DELTA#basic) was ex- pressed in transgenic mice under the control of the #beta#-actin promoter (BAPa#DELTA#basic). Three independent lines of BAPa#DELTA#basic transgenic mice all developed some degree of yellow pigment in the fur, indicating that the agouti#DELTA#basic protein was functional in vivo. However, none of the BAPa#DELTA#basic transgenic mice developed completely yellow fur, obesity, hyperinsulinemia, or hyperglycemia. High levels of agouti#DELTA#basic expression in relevant tissues exceeded the level of agouti expression in obese viable yellow mice, suggesting that suboptimal activity or synthesis of the agouti#DELTA#basic protein, rather than insufficient RNA synthesis, accounts for the phenotype of the BAPa#DELTA#basic transgenic mice. These findings implicate a functional role for the agouti basic domain in vivo, possibly influencing the biogenesis of secreted agouti protein or modulating protein-protein interactions that contribute t
机译：黑色素皮质激素受体对旁分泌作用的刺豚鼠基因产物的长期拮抗作用在泛滥表达野生型刺豚鼠的小鼠中诱发黄皮病和成熟期肥胖症候群。转基因小鼠中刺豚鼠突变的功能分析表明，体内刺豚鼠活性需要富含半胱氨酸的C末端，信号肽和糖基化位点。相反，没有生物学活性归因于保守的基本结构域。为了检查刺豚鼠基本结构域的功能重要性，从刺豚鼠cDNA中删除了整个29-aa区域，并在＃的控制下在转基因小鼠中表达了突变体（agouti＃DELTA＃basic）。 beta＃-肌动蛋白启动子（BAPa＃DELTA＃basic）。三个独立的BAPa＃DELTA＃碱性转基因小鼠品系均在毛皮中形成了一定程度的黄色色素，表明agouti＃DELTA＃碱性蛋白在体内具有功能。但是，BAPA＃DELTA＃基础转基因小鼠均未出现全黄皮毛，肥胖，高胰岛素血症或高血糖症。相关组织中高水平的agouti＃DELTA＃碱性表达超过了肥胖的存活黄色小鼠中agouti的表达水平，这表明agouti＃DELTA＃碱性蛋白的活性不足或合成不足，而不是RNA合成不足，解释了该蛋白的表型。 BAPA＃DELTA＃基本转基因小鼠。这些发现暗示了刺豚鼠基本结构域在体内的功能性作用，可能影响了分泌刺豚鼠蛋白质的生物发生或调节了促性腺激素的蛋白质-蛋白质相互作用。

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