Hypoxia regulates the degradation of non-nuclear organelles during lens differentiation through activation of HIF1a.
Hypoxia regulates the degradation of non-nuclear organelles during lens differentiation through activation of HIF1a.
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DOI：
10.1016/j.exer.2020.108129
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发表时间：
2020-09
影响因子：
3.4
通讯作者：
Kantorow M
中科院分区：
文献类型：
--
作者：
Brennan L;Disatham J;Kantorow M
眼透镜的形成依赖于透镜上皮细胞向透镜纤维细胞的连续分化。新生的透镜纤维细胞要获得成熟的结构和透明的功能，必须完成一个精确的细胞重塑程序，其特点是细胞器的完全消除，形成核心透镜无细胞器区（OFZ）。由于缺乏血液供应，透镜处于低氧环境中，这导致从透镜表面到透镜核心的氧浓度降低。该氧梯度导致透镜区域中的缺氧微环境，其中未成熟的透镜纤维细胞开始损失细胞器以形成核心OFZ。透镜的这些特征表明低透镜氧水平在调节细胞器降解和成熟透镜纤维细胞形成的其他关键事件中的潜在作用。低氧激活低氧反应的主要调节因子，低氧诱导因子1a（HIF 1a），其调节低氧反应基因。为了确定缺氧和HIF 1a在透镜纤维细胞成熟过程中消除细胞器的潜在作用，我们通过监测低（1%O2）和高（21%O2）氧条件下线粒体（MT）、高尔基体（GA）和内质网（ER）的降解，测试了离体培养的鸡胚晶状体中非核细胞器降解中缺氧的要求。我们还研究了在相同条件下使用特定的HIF 1a激活剂（DMOG）和特定的HIF 1a抑制剂（chetomin）消除这些细胞器对HIF 1a激活的要求，并研究了我们先前证明消除非核透镜细胞器所需的低氧和HIF 1a调节BNIP 3L转录的要求。最后，我们研究了表达氧不敏感突变形式的HIF 1a（P402 A/P565 A）和BNIP 3L对非核细胞器降解的影响。我们的数据表明，缺氧和HIF 1a的降解所需的非核细胞器在透镜纤维细胞的形成，他们调节这一过程中，通过管理BNIP 3L转录。我们的研究结果还提供了证据，缺氧和HIF 1a是必不可少的实现成熟的透镜结构。
Formation of the eye lens depends on the continuous differentiation of lens epithelial cells into lens fiber cells. To attain their mature structure and transparent function, nascent lens fiber cells must complete a precise cellular remodeling program hallmarked by the complete elimination of organelles to form the core lens organelle-free zone (OFZ). Lacking a blood supply, the lens resides in a hypoxic environment that results in a decreasing oxygen concentration from the lens surface to the lens core. This oxygen gradient results in a hypoxic microenvironment in the region of the lens where immature lens fiber cells initiate loss of organelles to form the core OFZ. These features of the lens suggest a potential role for low lens oxygen levels in the regulation of organelle degradation and other events critical for mature lens fiber cell formation. Hypoxia activates the master regulator of the hypoxic response, hypoxia-inducible factor 1a (HIF1a) that regulates hypoxia-responsive genes. To identify a potential role for hypoxia and HIF1a in the elimination of organelles during lens fiber cell maturation, we tested the requirement for hypoxia in the degradation of non-nuclear organelles in ex vivo cultured embryonic chick lenses by monitoring the degradation of mitochondria (MT), Golgi apparatus (GA) and endoplasmic reticulum (ER) under conditions of low (1% O2) and high (21% O2) oxygen. We also examined the requirement for HIF1a activation for elimination of these organelles under the same conditions using a specific HIF1a activator (DMOG) and a specific HIF1a inhibitor (chetomin) and examined the requirements for hypoxia and HIF1a for regulating transcription of BNIP3L that we previously showed to be required for elimination of non-nuclear lens organelles. Finally, we examined the effects of expressing an oxygen insensitive mutant form of HIF1a (P402A/P565A) and BNIP3L on non-nuclear organelle degradation. Our data demonstrate that hypoxia and HIF1a are required for degradation of non-nuclear organelles during lens fiber cell formation and that they regulate this process by governing BNIP3L transcription. Our results also provide evidence that hypoxia and HIF1a are essential for achieving mature lens structure.
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影响因子：
7.8
作者：
Bassnett, S;Mataic, D
通讯作者：
Mataic, D
影响因子：
3.4
作者：
Brennan LA;McGreal-Estrada R;Logan CM;Cvekl A;Menko AS;Kantorow M
通讯作者：
Kantorow M
影响因子：
5.1
作者：
Haring M;Offermann S;Danker T;Horst I;Peterhansel C;Stam M
通讯作者：
Stam M
影响因子：
5.5
作者：
McNulty, R;Huan, W;Bassnett, S
通讯作者：
Bassnett, S
影响因子：
5.3
作者：
Bellot, Gregory;Garcia-Medina, Raquel;Mazure, Nathalie M.
通讯作者：
Mazure, Nathalie M.