Molecular biology of retinal development and retinal degeneration

为探讨TGF-β超家族在视网膜发育中的作用，采用免疫组织化学方法观察了正常大鼠视网膜发育过程中TGF-β超家族受体表达的变化。激活素I型受体和BMP IB型受体首先分别在P6和P3视网膜中以蛋白质水平检测到，并且激活素II型受体首先在P0视网膜中检测到。其他受体（TGF-β I型和II型受体、激活素IB型受体、BMP IA型和II型受体）在E17时检测到。PO-P9期与大鼠视网膜发育的动态变化相一致。这些结果表明，TGF-β超家族的表达沿着视网膜的发育，可能与视网膜的发育有关。RB细胞系由于TGF-β与RB细胞结合的缺乏而对TGF-β具有抗性。为了阐明耐药机制， ...更多信息 针对TGF-β，我们研究了TGF-β受体和Smad家族（TGF-β家族的转换器）在细胞系中的表达，以及TGF-β RB的信号转导途径。在RB细胞系中，TGF-β I型或II型受体（分别为TbetaR-I、TbetaR-II）在细胞表面上不表达。表达TbetaR-I mRNA。未检测到TbetaR-II mRNA，但丁酸钠可诱导TbetaR-II mRNA的表达。突变分析显示TbetaR-II基因编码区无突变。表达Smad家族成员mRNA（Smad 2、3、4）。通过TGF-β添加的转录激活仅通过TbetaR-I和TbetaR-II两者的转染来拯救。对TGF-β的应答的缺乏是由细胞表面上TGF-β受体表达的缺乏引起的。RB细胞中某些信号转导通路是保守的，为探讨RCS大鼠视网膜变性的发病机制，研究RB细胞胞浆内凋亡信号转导分子的表达。凋亡信号调节激酶1（ASK 1）参与丝裂原活化蛋白（MAP）激酶级联反应。p38和具有MAP激酶活性的c-Jun-氨基末端激酶（JNK）是ASK 1的下游组分。4 W和5 W的RCS大鼠视网膜，p38和JNK在两个RCS大鼠的内节中表达。而RCS大鼠视网膜光感受器细胞内节区ASK 1、p38-p和JNK-p的表达均显著降低，提示RCS大鼠视网膜光感受器细胞内ASK 1通过p38和/或JNK的信号转导被阻断。RCS大鼠视网膜光感受器细胞中ASK 1通过p38和/或JNK的信号转导被阻断。少

To ascertain the roles of TGF-beta superfamily in retinal development, the changes of the expression patterns of these receptors during development of the normal rat retina were observed immunohistochemically. Activin type I receptor and BMP type IB receptor were first detected in P6 and P3 retinas at protein levels, respectively, and activin type II receptor was First detected in P0 retina The other receptors (TGF-beta type I and II receptors, activin type IB receptor, BMP type IA and II receptors) were detected at E17. The period of PO-P9 corresponded to the dynamic changes in the rat retinal development. These results suggest that the expression of TGF-beta superfamily is regulated along with retinal development and may be related to retinal developmentTo investigate molecular mechanisms of retinal precursor cells, retinoblastoma (RB) cell lines were used. RB cell lines are resistant to TGF-beta due to the absence of TGF-beta binding to RB cells. To elucidate the mechanisms of resis … More tance to TGF-beta, we studied the expression of TGF-beta receptors and Smad family (transducers for TGF-beta family), and signal transduction pathways for TGF-beta RB in cell lines. In RB cell lines, either TGF-beta type I or II receptors (TbetaR-I, TbetaR-II, respectively) was not expressed on the cell surface. TbetaR-I mRNA was expressed. TbetaR-II mRNA was not detected, however, was induced by sodium butyrate. Mutation analysis revealed no mutation in the coding region of TbetaR-II gene. Smad family member mRNAs (Smad 2, 3, 4) were expressed. Transcription activation by TGF-beta addition was rescued only by the transfection of both TbetaR-I and TbetaR-II.The lack of response to TGF-beta is caused by the lack of TGF-beta receptor expression on cell surface. Some parts of signal transduction pathways are conserved in RB cells.To investigate pathogenesis of retinal degeneration in Royal College of Surgeons (RCS) rats in vivo, the expression of intracytoplasmic signal transducers for apoptosis. Apoptosis signal-regulating kinase 1 (ASK1) in involved in the mitogen-activated protein (MAP) kinase cascade. p38 and c-Jun-amino-terminal kinase (JNK) with MAP kinase activity were downstream component of ASK1. RCS rat retina of 4W and 5W, p38 and JNK were expressed in the inner segments in both RCS rats. However, the expression of ASK1, p38-p or JNK-p in the inner segments decreased significantly in RCS rats, which suggests that the signal transduction from ASK1 through p38 and/or JNK was abrogated in RCS rat retinal photoreceptor cells. Signal transduction from ASK1 through p38 and/or JNK was abrogated in retinal photoreceptor cells in RCS rat. Less