PEDF Gene Deletion Disrupts Corneal Innervation and Ocular Surface Function.
PEDF Gene Deletion Disrupts Corneal Innervation and Ocular Surface Function.
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PEDF基因缺失破坏角膜神经支配和眼表功能
DOI：
10.1167/iovs.62.7.18
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发表时间：
2021-06-01
影响因子：
4.4
通讯作者：
Tombran-Tink J
中科院分区：
文献类型：
--
作者：
Shang Z;Li C;Liu X;Xu M;Zhang X;Li X;Barnstable CJ;Zhao S;Tombran-Tink J
角膜由三叉神经节（TG）丰富地支配，并且其功能由来自邻近泪腺（LG）和睑板腺（MG）的分泌物支持。在这项研究中，我们研究了色素上皮衍生因子（PEDF）基因缺失如何影响角膜的结构和功能。我们使用PEDF半合子和纯合子敲除小鼠研究PEDF缺乏对角膜神经支配的影响，通过β微管蛋白染色、营养因子的mRNA表达和相邻支持腺体的PEDF受体、使用Cochet-Bonnet触觉计测量的角膜敏感性和使用酚红棉线润湿的泪液产生来评估。PEDF的丧失伴随着角膜神经支配和敏感性降低、角膜表面损伤和泪液产生增加、角膜基质变薄和基质细胞丧失。PEDF mRNA在角膜及其支持组织、TG、LG和MG中均有表达。缺失一个或两个PEDF等位基因导致TG、LG和MG中的基本营养支持表达降低，包括神经生长因子、脑源性神经营养生长因子和GDNF，LG中的NT-3水平显著升高，角膜中的EGF表达降低。在TG、LG和MG中，推定的PEDF受体、脂肪甘油三酯脂肪酶、脂蛋白受体相关蛋白6、层粘连蛋白受体、PLXDC 1和PLXDC 2的转录降低也很明显，与野生型对照组相比，前三种在Pedf+/−和Pedf−/−小鼠的角膜中显示出增加的水平。ERK 1/2和Akt的组成性失活在TG和角膜中是明显的，尽管它们的蛋白水平在Pedf−/−小鼠中显著增加。这项研究强调了PEDF在角膜结构和功能中的重要作用，并证实了所报道的外源性PEDF治疗在角膜病理学中的拯救作用。PEDF缺失对多种营养因子、受体和信号传导分子的多效性作用强烈表明PEDF是维持角膜功能的分子机制的关键协调者，并且可以用于几种眼表疾病的治疗选择。
The cornea is richly innervated by the trigeminal ganglion (TG) and its function supported by secretions from the adjacent lacrimal (LG) and meibomian glands (MG). In this study we examined how pigment epithelium–derived factor (PEDF) gene deletion affects the cornea structure and function. We used PEDF hemizygous and homozygous knockout mice to study effects of PEDF deficiency on corneal innervation assessed by beta tubulin staining, mRNA expression of trophic factors, and PEDF receptors by adjacent supporting glands, corneal sensitivity measured using a Cochet-Bonnet esthesiometer, and tear production using phenol red cotton thread wetting. Loss of PEDF was accompanied by reduced corneal innervation and sensitivity, increased corneal surface injury and tear production, thinning of the corneal stroma and loss of stromal cells. PEDF mRNA was expressed in the cornea and its supporting tissues, the TG, LG, and MG. Deletion of one or both PEDF alleles resulted in decreased expression of essential trophic support in the TG, LG, and MG including nerve growth factor, brain-derived neurotrophic growth factor, and GDNF with significantly increased levels of NT-3 in the LG and decreased EGF expression in the cornea. Decreased transcription of the putative PEDF receptors, adipose triglyceride lipase, lipoprotein receptor–related protein 6, laminin receptor, PLXDC1, and PLXDC2 was also evident in the TG, LG and MG with the first three showing increased levels in corneas of the Pedf+/− and Pedf−/− mice compared to wildtype controls. Constitutive inactivation of ERK1/2 and Akt was pronounced in the TG and cornea, although their protein levels were dramatically increased in Pedf−/− mice. This study highlights an essential role for PEDF in corneal structure and function and confirms the reported rescue of exogenous PEDF treatment in corneal pathologies. The pleiotropic effects of PEDF deletion on multiple trophic factors, receptors and signaling molecules are strong indications that PEDF is a key coordinator of molecular mechanisms that maintain corneal function and could be exploited in therapeutic options for several ocular surface diseases.
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影响因子：
5.6
作者：
Bürger S;Meng J;Zwanzig A;Beck M;Pankonin M;Wiedemann P;Eichler W;Unterlauft JD
通讯作者：
Unterlauft JD
影响因子：
4.4
作者：
De Silva, Manikkuwadura Eranda Harshan;Hill, Lisa J.;Chinnery, Holly R.
通讯作者：
Chinnery, Holly R.
影响因子：
4.6
作者：
Ma L;Tang SM;Rong SS;Chen H;Young AL;Kumaramanickavel G;Pang CP;Chen LJ
通讯作者：
Chen LJ
影响因子：
4.4
作者：
Gonzalez-Coto, Ana F.;Alonso-Ron, Carlos;Belmonte, Carlos
通讯作者：
Belmonte, Carlos
影响因子：
4.4
作者：
Amaral J;Becerra SP
通讯作者：
Becerra SP