This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Determining the molecular mechanisms involved in the differentiation of post mitotic cells such as striated muscle cells, will be crucial for understanding and controlling the way in which tissue regeneration occurs and extremely valuable for the use of stem cell therapies. Master regulators likely play a key role in assuring normal development of tissue-specific structures and function, some of which must link differentiation signaling to pathways which regulate both apoptosis and cell cycle withdrawl. Though the mechanisms which regulate these complex signalling networks are by and large not understood, posttranslational modification of proteins by phosphorylation, acetylation and ubiquitylation, as well as alternative splicing of mRNA transcripts are essential for generating the precise spacio-temporal patterns of protein activation which are required. Ufd2a is critical to cell division and may also participate in apoptosis signalling. In addition, while undifferentiated myoblasts express exclusively a shorter, ubiquitous form of Ufd2a, fully differentiated cardiac and skeletal muscle cells express a larger, alternatively spliced isoform. Ufd2a appears to be critical to normal development of the heart as Ufd2a -/- mice die in utero with multiple heart defects. The goal of this proposal is to define the spacio-temporal regulation of Ufd2a by alternative splicing, and to determine the functional significance of these tissue-specific isoforms in the process of development and differentiation. These studies may provide insights into how non-dividing cells may employ critical cell cycle effectors for novel functions during their differentiation and lead to a better understanding of the mechanisms of cardiac and skeletal muscle development.
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