The Role of Alternative Splicing of Ufd2a in Differentiation (2006 - Present)

Investigator:  Sarah Spinette, Rhode Island College
Mentor:  Kenneth Walsh, Boston University School of Medicine 

Abstract:  Determining the molecular mechanisms involved in the differentiation of post-mitotic cells such as striated muscle cells and neurons, 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 withdrawal.  Though the mechanisms which regulate these complex signaling networks are by and large not understood, post-translational 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 (1-3). Ufd2a may be a ubiquitylation enzyme which stands at the interface of these regulatory mechanisms. Ufd2a is critical to cell division and may also participate in apoptosis signaling (4). In addition, while undifferentiated myoblasts express exclusively a shorter, ubiquitous form of Ufd2a, differentiated cardiac and skeletal muscle cells of humans and rodents express a larger, alternatively spliced isoform. Ufd2a appears to be critical to normal development of the heart as Ufd2-/- 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 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 and neurodegeneration. The proposed experiments will address the following specific aims: 

Specific aim 1: Determine the expression pattern of the various alternatively spliced isoforms of Ufd2a across human and murine tissue types and differentiation stages. 

Specific aim 2: Define the function of novel Ufd2a isoforms.