Bhattacharyya Mahamaya, Nandanoor Anoop, Osman Mohammad, Kasinathan Chinnaswamy, Frederikse Peter
Neurochem Res. 2014 Sep;39(9):1825-32. doi: 10.1007/s11064-014-1394-z. Epub 2014 Jul 29.
Detailed parallels described between lens fiber cell and neuron morphology, sub-cellular structure, and molecular biology include striking similarities in the ultrastructure of their vesicle transport machinery and the membrane protrusions that occur along the lateral surfaces of both cell types. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate receptor (NMDA) glutamate receptors (AMPARs/NMDARs) are the predominant receptors in neurons. These receptors have fundamental roles in neuron morphogenesis as well as neuron physiology and dynamic cell signaling, and specifically at dendritic spines. As a result, AMPAR and NMDAR dysregulation underlies several primary neural disorders that have also shown epidemiological associations with cataract. Previously, we demonstrated AMPAR GluA1 and REST (RE-1 silencing transcription factor)-regulated GluA2 subunits are expressed in the lens, and showed C-terminal phospho-tyrosine-GluA2, and striatal-enriched tyrosine phosphatase (STEP), as well as GluA2 Q/R RNA editing in lenses similar to neurons. Here, we demonstrated that REST-regulated NMDAR NR1, NR2A, and NR2B are also expressed in lenses and localize predominantly in fiber cell membranes, consistent with REST transcription factors, as well as miR-124 and other REST gene targets identified in the lens. We also showed NR2B Tyr-1472 phosphorylation occurs in lens. These p-Tyr-GluA2 and p-Tyr-NR2B phosphorylation events are linked with membrane insertion regulated by STEP. We next determined that NR1 transcripts that include exon 5 are produced in lens consistent with Fox-1 RNA binding protein isoforms linked with this alternative splicing event, and shown to be expressed in lens as well as brain. These findings provide further evidence that fundamental neuronal morphogenetic programs, and hallmark neuronal gene expression and modes of regulation, are shared with elongated fiber cells of the lens.
晶状体纤维细胞与神经元在形态、亚细胞结构和分子生物学方面存在详细的相似之处，包括它们囊泡运输机制的超微结构以及两种细胞类型侧面出现的膜突起具有惊人的相似性。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和N-甲基-D-天冬氨酸受体（NMDA）谷氨酸受体（AMPARs/NMDARs）是神经元中的主要受体。这些受体在神经元形态发生以及神经元生理学和动态细胞信号传导中起着基本作用，特别是在树突棘处。因此，AMPAR和NMDAR失调是几种原发性神经疾病的基础，这些疾病在流行病学上也与白内障有关。此前，我们证明了AMPAR GluA1和REST（RE-1沉默转录因子）调节的GluA2亚基在晶状体中表达，并显示出C端磷酸化酪氨酸-GluA2、纹状体富集酪氨酸磷酸酶（STEP）以及晶状体中与神经元相似的GluA2 Q/R RNA编辑。在这里，我们证明了REST调节的NMDAR NR1、NR2A和NR2B也在晶状体中表达，并且主要定位于纤维细胞膜，这与REST转录因子以及晶状体中鉴定出的miR-124和其他REST基因靶点一致。我们还表明NR2B Tyr-1472磷酸化发生在晶状体中。这些p-Tyr-GluA2和p-Tyr-NR2B磷酸化事件与STEP调节的膜插入有关。接下来，我们确定晶状体中产生了包含外显子5的NR1转录本，这与与这种可变剪接事件相关的Fox-1 RNA结合蛋白异构体一致，并且已证明在晶状体和大脑中均有表达。这些发现进一步证明，基本的神经元形态发生程序以及标志性的神经元基因表达和调节模式与晶状体的细长纤维细胞是共有的。
