Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.
Universitat Pompeu Fabra, Barcelona, Spain.
Mol Syst Biol. 2024 Apr;20(4):296-310. doi: 10.1038/s44320-024-00020-1. Epub 2024 Mar 4.
Alternative Splicing (AS) programs serve as instructive signals of cell type specificity, particularly within the brain, which comprises dozens of molecularly and functionally distinct cell types. Among them, retinal photoreceptors stand out due to their unique transcriptome, making them a particularly well-suited system for studying how AS shapes cell type-specific molecular functions. Here, we use the Splicing Regulatory State (SRS) as a novel framework to discuss the splicing factors governing the unique AS pattern of photoreceptors, and how this pattern may aid in the specification of their highly specialized sensory cilia. In addition, we discuss how other sensory cells with ciliated structures, for which data is much scarcer, also rely on specific SRSs to implement a proteome specialized in the detection of sensory stimuli. By reviewing the general rules of cell type- and tissue-specific AS programs, firstly in the brain and subsequently in specialized sensory neurons, we propose a novel paradigm on how SRSs are established and how they can diversify. Finally, we illustrate how SRSs shape the outcome of mutations in splicing factors to produce cell type-specific phenotypes that can lead to various human diseases.
可变剪接 (AS) 程序可作为细胞类型特异性的指导信号，尤其是在大脑中，大脑包含数十种在分子和功能上明显不同的细胞类型。其中，视网膜光感受器因其独特的转录组而引人注目，这使得它们成为研究 AS 如何塑造细胞类型特异性分子功能的特别合适的系统。在这里，我们使用剪接调控状态 (SRS) 作为一个新的框架来讨论调控光感受器独特 AS 模式的剪接因子，以及这种模式如何有助于其高度特化的感觉纤毛的特化。此外，我们还讨论了其他具有纤毛结构的感觉细胞，这些细胞的数据要少得多，它们如何也依赖于特定的 SRS 来实施专门用于检测感觉刺激的蛋白质组。通过回顾大脑中以及专门的感觉神经元中的细胞类型和组织特异性 AS 程序的一般规则，我们提出了一个关于 SRS 如何建立以及如何多样化的新范例。最后，我们说明了 SRS 如何影响剪接因子突变的结果，产生具有特定细胞类型表型的突变，从而导致各种人类疾病。
