Deletion of transcription factor AP-2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes.
Deletion of transcription factor AP-2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes.
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DOI：
10.1002/jnr.24982
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发表时间：
2022-03
影响因子：
4.2
通讯作者：
West-Mays JA
中科院分区：
文献类型：
--
作者：
Taiyab A;Akula M;Dham J;Deschamps P;Sheardown H;Williams T;Borrás T;West-Mays JA
青光眼是不可逆失明的主要原因之一，并且可以由房水流出所需的前段结构的异常引起，包括小梁网（TM）和施累姆氏管（SC）。转录因子如AP-2β在眼前节发育中起关键作用。在这里，我们表明，Mgp-Cre基因敲入（Mgp-Cre.KI）小鼠可用于靶向胚胎眼周间充质，从而产生TM和SC。雄性和雌性小鼠的命运作图表明，AP-2β缺失导致与对照组相比，来自Mgp-Cre. KI表达群体的虹膜角细胞减少。此外，组织学分析显示AP-2β突变体的周边虹膜角膜粘连伴随TM和SC标志物表达的减少，如使用免疫组织化学观察到的。此外，与对照组相比，反跳眼压测量显示AP-2β突变体的眼内压（IOP）显著升高，这与视网膜神经节细胞进行性显著丢失、视网膜厚度减少和视网膜功能降低相关（使用视网膜电图测量），反映了晚期青光眼患者中描述的病理。重要的是，AP-2β突变体的IOP升高通过拉坦前列素治疗显著降低，拉坦前列素是一种增加非常规流出的前列腺素类似物。这些发现表明AP-2β对TM和SC的发展至关重要，这些突变小鼠可以作为理解和治疗进行性人类原发性闭角型青光眼的模型。
Glaucoma is one of the leading causes of irreversible blindness and can result from abnormalities in anterior segment structures required for aqueous humor outflow, including the trabecular meshwork (TM) and Schlemm’s canal (SC). Transcription factors such as AP-2β play critical roles in anterior segment development. Here, we show that the Mgp-Cre knock-in (Mgp-Cre.KI) mouse can be used to target the embryonic periocular mesenchyme giving rise to the TM and SC. Fate mapping of male and female mice indicates that AP-2β loss causes a decrease in iridocorneal angle cells derived from Mgp-Cre.KI-expressing populations compared to controls. Moreover, histological analyses revealed peripheral iridocorneal adhesions in AP-2β mutants that were accompanied by a decrease in expression of TM and SC markers, as observed using immunohistochemistry. In addition, rebound tonometry showed significantly higher intraocular pressure (IOP) that was correlated with a progressive significant loss of retinal ganglion cells, reduced retinal thickness, and reduced retinal function, as measured using an electroretinogram, in AP-2β mutants compared with controls, reflecting pathology described in late-stage glaucoma patients. Importantly, elevated IOP in AP-2β mutants was significantly reduced by treatment with latanoprost, a prostaglandin analog that increases unconventional outflow. These findings demonstrate that AP-2β is critical for TM and SC development, and that these mutant mice can serve as a model for understanding and treating progressive human primary angle-closure glaucoma.
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影响因子：
3.4
作者：
Akula M;Taiyab A;Deschamps P;Yee S;Ball AK;Williams T;West-Mays JA
通讯作者：
West-Mays JA
影响因子：
20.1
作者：
Choi D;Park E;Jung E;Seong YJ;Hong M;Lee S;Burford J;Gyarmati G;Peti-Peterdi J;Srikanth S;Gwack Y;Koh CJ;Boriushkin E;Hamik A;Wong AK;Hong YK
通讯作者：
Hong YK
影响因子：
4.4
作者：
Asokan P;Mitra RN;Periasamy R;Han Z;Borrás T
通讯作者：
Borrás T
DOI：
10.2147/opth.s59162
发表时间：
2014
期刊：
Clinical ophthalmology (Auckland, N.Z.)
影响因子：
--
作者：
Alm A
通讯作者：
Alm A
影响因子：
4.4
作者：
Chen L;Gage PJ
通讯作者：
Gage PJ