Regulation of protein diversity by alternative pre-mRNA splicing with specific focus on chondrogenesis.

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. Copyright 2004 Wiley-Liss, Inc.