Altered pancreatic islet function and morphology in mice lacking the Beta-cell surface protein neuroligin-2.
Altered pancreatic islet function and morphology in mice lacking the Beta-cell surface protein neuroligin-2.
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DOI：
10.1371/journal.pone.0065711
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chessler SD
中科院分区：
文献类型：
--
作者：
Zhang C;Suckow AT;Chessler SD
Neuroligin-2 是一种跨膜细胞表面蛋白，最初被鉴定为中枢神经系统中的抑制性突触相关蛋白。 Neuroligin-2 也存在于胰腺 β 细胞表面，它参与跨细胞相互作用，驱动胰岛素分泌机制的功能成熟；这些是正常胰岛素分泌所必需的。使用 Neuroligin-2 敲除小鼠，已经广泛表征了 Neuroligin-2 缺乏对大脑和神经元功能和形态以及行为和协调的影响。然而，Neuroligin-2 表达缺失对胰岛发育和功能的影响尚不清楚。在这里，为了帮助测试 Neuroligin-2 是否是正常胰岛发育所必需的，我们对缺乏 Neuroligin-2 的小鼠的胰岛形态进行了表征。为了测试是否如我们早期共培养研究所预测的那样，neuroligin-2 的缺失会损害 β 细胞功能，我们比较了突变型和野生型小鼠的胰岛在葡萄糖刺激下的胰岛素分泌。我们的结果表明，虽然来自 Neuroligin-2 缺陷小鼠的胰岛在结构上与野生型胰岛似乎没有差异，但它们更小、数量更少，并且含有胰岛素含量较低的 β 细胞。转录水平的评估表明，neuroligin-1 的上调有助于补偿 Neuroligin-2 的损失。令人惊讶的是，在基础葡萄糖水平和刺激葡萄糖水平下，来自基因敲除小鼠的分离胰岛分泌更多的细胞内胰岛素含量。 shRNA 介导的 Neuroligin-2 敲低的大鼠胰岛也表现出胰岛素分泌增加。基因敲除小鼠中的神经毒素转录水平较低，并且与我们之前的发现一致，即神经毒素是胰岛素颗粒对接机制的关键组成部分，胰岛素颗粒对接减少了。这些结果表明，neuroligin-2对于胰岛的形成不是必需的，但neuroligin-2影响胰岛的大小和数量。 Neuroligin-2——或许通过其对其结合伙伴神经素的表达和/或活性的影响——促进胰岛素颗粒对接，这是胰岛素分泌的已知限制。
Neuroligin-2 is a transmembrane, cell-surface protein originally identified as an inhibitory synapse-associated protein in the central nervous system. Neuroligin-2 is also present on the pancreatic beta-cell surface, and there it engages in transcellular interactions that drive functional maturation of the insulin secretory machinery; these are necessary for normal insulin secretion. The effects of neuroligin-2 deficiency on brain and neuronal function and morphology and on behavior and coordination have been extensively characterized using neuroligin-2 knockout mice. The effects of absent neuroligin-2 expression on islet development and function, however, are unknown. Here, to help test whether neuroligin-2 is necessary for normal islet development, we characterized islet morphology in mice lacking neuroligin-2. To test whether–as predicted by our earlier co-culture studies–absence of neuroligin-2 impairs beta cell function, we compared glucose-stimulated insulin secretion by islets from mutant and wild-type mice. Our results show that while islets from neuroligin-2-deficient mice do not to appear to differ architecturally from wild-type islets, they are smaller, fewer in number, and contain beta cells with lower insulin content. Evaluation of transcript levels suggests that upregulation of neuroligin-1 helps compensate for loss of neuroligin-2. Surprisingly, under both basal and stimulating glucose levels, isolated islets from the knockout mice secreted more of their intracellular insulin content. Rat islets with shRNA-mediated neuroligin-2 knockdown also exhibited increased insulin secretion. Neurexin transcript levels were lower in the knockout mice and, consistent with our prior finding that neurexin is a key constituent of the insulin granule docking machinery, insulin granule docking was reduced. These results indicate that neuroligin-2 is not necessary for the formation of pancreatic islets but that neuroligin-2 influences islet size and number. Neuroligin-2–perhaps through its effects on the expression and/or activity of its binding partner neurexin–promotes insulin granule docking, a known constraint on insulin secretion.
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DOI：
10.1083/jcb.144.2.325
发表时间：
1999-01-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Esni F;Täljedal IB;Perl AK;Cremer H;Christofori G;Semb H
通讯作者：
Semb H
影响因子：
2.2
作者：
Huang, Han-Hung;Novikova, Lesya;Stehno-Bittel, Lisa
通讯作者：
Stehno-Bittel, Lisa
影响因子：
7.7
作者：
Kwan, EP;Xie, L;Gaisano, HY
通讯作者：
Gaisano, HY
影响因子：
3.5
作者：
Chih, B;Afridi, SK;Scheiffele, P
通讯作者：
Scheiffele, P
影响因子：
8.2
作者：
Grouwels, G.;Vasylovska, S.;Heimberg, H.
通讯作者：
Heimberg, H.