Hennig Anne K, Peng Guang-Hua, Chen Shiming
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Brain Res. 2008 Feb 4;1192:114-33. doi: 10.1016/j.brainres.2007.06.036. Epub 2007 Jun 30.
Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor beta2 (Tr beta2), retinoid related orphan receptor Ror beta, and retinoid X receptor Rxr gamma. The appropriate function of this network also depends on general transcription factors and cofactors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA co-activator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development, and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.
哺乳动物视网膜中的视杆和视锥光感受器是特殊类型的神经元，负责光转导，即视觉的第一步。光感受器的发育和维持需要精确调控的基因表达。这种调控由以Crx为中心的光感受器转录因子网络介导，Crx是一种Otx样同源域转录因子。该网络的细胞类型（亚型）特异性由视杆或视锥或两者优先表达的因子决定，包括决定视杆的因子神经视网膜亮氨酸拉链蛋白（Nrl）和孤儿核受体Nr2e3；以及决定视锥的因子，主要是核受体家族成员。其中记录最详尽的包括甲状腺激素受体β2（Trβ2）、类视黄醇相关孤儿受体Rorβ和类视黄醇X受体Rxrγ。该网络的适当功能还取决于普遍表达的一般转录因子和辅因子，如Sp锌指转录因子和STAGA共激活复合物。这些细胞类型特异性和一般转录调节因子形成复杂的相互作用组；干扰任何相互作用的突变都可能导致光感受器发育缺陷或退化。在本手稿中，我们综述了各种光感受器转录因子的作用以及它们在光感受器亚型发育中的相互作用的最新进展。我们还提供了这些因子在转录水平上的自调控、旁调控和反馈调控的证据。这些蛋白质-蛋白质和蛋白质-启动子相互作用在控制光感受器亚型特异性基因表达、发育和存活方面提供了精确性和特异性。了解这些相互作用可能为光感受器疾病提供更有效的治疗干预方法。
