Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2
Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2
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DOI：
10.1073/pnas.94.13.6646
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发表时间：
1997-06-24
影响因子：
11.1
通讯作者：
Steiner, DF
中科院分区：
文献类型：
--
作者：
Furuta, M;Yano, H;Steiner, DF
前激素转换酶SPC2(PC2)参与胰岛素原、胰高血糖素原和其他多种神经内分泌前体的加工，可以单独作用，也可以与结构上相关的致密核心颗粒转换酶SPC3(PC3/PC1)共同作用。我们通过将新霉素抗性基因(neo(R))导入mSPC2基因的第三外显子，产生了一种缺乏活性SPC2的小鼠，这种基因插入导致合成了外显子3缺失的SPC2，该SPC2不进行自动激活和分泌，纯合子突变小鼠在出生时看起来是正常的，但他们的生长速度略有下降。他们还存在慢性空腹低血糖和腹膜糖耐量试验中血糖水平升高的减少，这与循环中胰高血糖素缺乏一致，胰高血糖素原、生长抑素原和胰岛素原的处理分别来自胰岛的α、β和β细胞严重受损，突变小鼠3个月龄的胰岛表现为显著的α和β细胞增殖和β细胞的相对减少。SPC2缺陷小鼠为进一步描述神经内分泌前体处理机制和更充分地探索许多神经肽和多肽激素的生理作用提供了许多可能性。
The prohormone convertase SPC2 (PC2) participates in the processing of proinsulin, proglucagon, and a variety of other neuroendocrine precursors, acting either alone or in conjunction with the structurally related dense-core granule convertase SPC3 (PC3/PC1). We have generated a strain of mice lacking active SPC2 by introducing the neomycin resistance gene (Neo(r)) into the third exon of the mSPC2 gene, This gene insertion results in the synthesis of an exon 3-deleted form of SPC2 that does not undergo autoactivation and is not secreted, The homozygous mutant mice appear to be normal at birth, However they exhibit a small decrease in rate of growth. They also have chronic fasting hypoglycemia and a reduced rise in blood glucose levels during an intraperitoneal glucose tolerance test, which is consistent with a deficiency of circulating glucagon, The processing of proglucagon, prosomatostatin, and proinsulin ire the alpha, delta, and beta cells, respectively, of the pancreatic islets is severely impaired, The islets in mutant mice at 3 months of age show marked hyperplasia of alpha and delta cells and a relative diminution of beta cells. SPC2-defective mice offer many possibilities for further delineating neuroendocrine precursor processing mechanisms and for exploring more fully the physiological roles of many neuropeptides and peptide hormones.