McAlinden Audrey, Havlioglu Necat, Sandell Linda J
Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Birth Defects Res C Embryo Today. 2004 Mar;72(1):51-68. doi: 10.1002/bdrc.20004.
Analysis of the human genome has dramatically demonstrated that the majority of protein diversity is generated by alternative splicing of pre-mRNA. This powerful and versatile mechanism controls the synthesis of functionally different protein isoforms that may be required during specific stages of development from a single gene. Consequently, ubiquitous and/or tissue-specific RNA splicing factors that regulate this splicing mechanism provide the basis for defining phenotypic characteristics of cells during differentiation. In this review, we will introduce the basic mechanisms of pre-mRNA alternative splicing, describe how this process is regulated by specific RNA splicing factors, and relate this to various systems of cell differentiation. Chondrogenesis, a well-defined differentiation pathway necessary for skeletogenesis, will be discussed in detail, with focus on some of the alternatively-spliced proteins known to be expressed during cartilage development. We propose a heuristic view that, ultimately, it is the regulation of these RNA splicing factors that determines the differentiation status of a cell. Studying regulation at the level of pre-mRNA alternative splicing will provide invaluable insights into how many developmental mechanisms are controlled, thus enabling us to manipulate a system to select for a specific differentiation pathway.
对人类基因组的分析已有力地证明，大多数蛋白质多样性是由前体mRNA的可变剪接产生的。这种强大且通用的机制控制着功能不同的蛋白质异构体的合成，这些异构体可能是单个基因在特定发育阶段所必需的。因此，调节这种剪接机制的普遍存在和/或组织特异性的RNA剪接因子，为定义细胞分化过程中的表型特征提供了基础。在本综述中，我们将介绍前体mRNA可变剪接的基本机制，描述该过程如何由特定的RNA剪接因子调控，并将其与各种细胞分化系统联系起来。软骨形成是骨骼形成所必需的一个明确的分化途径，将进行详细讨论，重点关注一些已知在软骨发育过程中表达的可变剪接蛋白。我们提出一种启发式观点，即最终是这些RNA剪接因子的调控决定了细胞的分化状态。研究前体mRNA可变剪接水平的调控，将为许多发育机制如何受到控制提供宝贵的见解，从而使我们能够操纵一个系统以选择特定的分化途径。
