Damage-induced neuronal endopeptidase (DINE) enhances axonal regeneration potential of retinal ganglion cells after optic nerve injury.
Damage-induced neuronal endopeptidase (DINE) enhances axonal regeneration potential of retinal ganglion cells after optic nerve injury.
复制标题
损伤诱导的神经元内肽酶（DINE）在视神经损伤后增强了视网膜神经节细胞的轴突再生潜力。
DOI：
10.1038/cddis.2017.212
复制
发表时间：
2017-06-01
影响因子：
9
通讯作者：
Kiyama H
中科院分区：
文献类型：
--
作者：
Kaneko A;Kiryu-Seo S;Matsumoto S;Kiyama H
损伤诱导的神经元内肽酶 (DINE)/内皮素转换酶样 1 (ECEL1) 是一种膜结合金属蛋白酶，我们将其鉴定为神经再生相关分子。 DINE 的表达因周围和中枢神经系统的神经损伤而上调，而其转录则受到激活转录因子 3 (ATF3) 的调节，ATF3 是神经再生的有效中枢转录因子。尽管 DINE 具有损伤诱导上调的独特特征，但其在受损神经元中的生理相关性尚不清楚。在本研究中，我们证明视神经损伤后受损的视网膜神经节细胞（RGC）中 DINE 的表达与 ATF3 的表达呈协调上调，而在任何正常视网膜细胞中均未观察到 DINE 和 ATF3。最近，我们培育了一种成熟的 DINE 缺陷（KOTg）小鼠，其中外源性 DINE 在胚胎运动神经元中特异性过度表达，以避免传统 DINE KO 小鼠中发生的运动神经异常树枝化和出生后致死。 DINE KOTg 小鼠在视网膜结构和大脑投射方面与正常条件下的野生型（野生型）小鼠没有表现出任何差异。然而，即使经过酵母聚糖（一种众所周知的再生促进剂）处理后，DINE KOTg 小鼠受损的 RGC 也无法再生。此外，DINE KOTg 小鼠与 Atf3:BAC Tg 小鼠杂交，其中绿色荧光蛋白 (GFP) 在受损的 RGC 和视神经中特异性显现，已证实 DINE 缺陷会导致再生失败。这些发现表明，损伤诱导的 DINE 是受损 RGC 的重要内肽酶，可促进视神经损伤后的轴突再生。因此，DINE 介导的蛋白水解机制将为我们提供一种新的神经再生治疗策略。
Damage-induced neuronal endopeptidase (DINE)/endothelin-converting enzyme-like 1 (ECEL1) is a membrane-bound metalloprotease that we identified as a nerve regeneration-associated molecule. The expression of DINE is upregulated in response to nerve injury in both the peripheral and central nervous systems, while its transcription is regulated by the activating transcription factor 3 (ATF3), a potent hub-transcription factor for nerve regeneration. Despite its unique hallmark of injury-induced upregulation, the physiological relevance of DINE in injured neurons has been unclear. In this study, we have demonstrated that the expression of DINE is upregulated in injured retinal ganglion cells (RGCs) in a coordinated manner with that of ATF3 after optic nerve injury, whereas DINE and ATF3 are not observed in any normal retinal cells. Recently, we have generated a mature DINE-deficient (KOTg) mouse, in which exogenous DINE is overexpressed specifically in embryonic motor neurons to avoid aberrant arborization of motor nerves and lethality after birth that occurs in the conventional DINE KO mouse. The DINE KOTg mice did not show any difference in retinal structure and the projection to brain from that of wild–type (wild type) mice under normal conditions. However, injured RGCs of DINE KOTg mice failed to regenerate even after the zymosan treatment, which is a well-known regeneration-promoting reagent. Furthermore, a DINE KOTg mouse crossed with a Atf3:BAC Tg mouse, in which green fluorescent protein (GFP) is visualized specifically in injured RGCs and optic nerves, has verified that DINE deficiency leads to regeneration failure. These findings suggest that injury-induced DINE is a crucial endopeptidase for injured RGCs to promote axonal regeneration after optic nerve injury. Thus, a DINE-mediated proteolytic mechanism would provide us with a new therapeutic strategy for nerve regeneration.
登录
查看更多内容
影响因子：
9.8
作者：
McMillin, Margaret J.;Below, Jennifer E.;Bamshad, Michael J.
通讯作者：
Bamshad, Michael J.
影响因子：
82.9
作者：
Breckwoldt, Michael;Pfister, Franz M. J.;Misgeld, Thomas
通讯作者：
Misgeld, Thomas
影响因子：
4.8
作者：
Kiryu-Seo S;Kiyama H
通讯作者：
Kiyama H
影响因子：
3.4
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Kim, Jessica;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
5.3
作者：
Nagata, Kenichi;Kiryu-Seo, Sumiko;Kiyama, Hiroshi
通讯作者：
Kiyama, Hiroshi