MicroRNAs influence tissue‐specific alternative splicing

Alternative splicing dramatically affects the gene expression patterns unique to differentiated cells. The splicing factors that control the ensembles of exons required in a specialized cell are themselves dynamically regulated. The polypyrimidine tract binding protein (PTB) and its close homolog neural PTB (nPTB) are two such proteins that influence the splicing of many exons in different tissues. We have found that the muscle‐specific microRNA miR‐133 represses nPTB protein expression during differentiation of myoblasts into myotubes and that miR‐133 thus affects the splicing of multiple muscle‐specific exons. In the brain, we find that posttranscriptional regulation of PTB and nPTB results in the divergent expression of the two proteins, leading to the reprogramming of alternative splicing patterns for many exons that participate in the functions of the mature cell types. The brain‐specific microRNA miR‐124 has been shown to participate in the control of PTB and nPTB protein expression, thereby affecting alternative splicing patterns in the adult brain. We are investigating the timing and regulation of miR‐124 biogenesis in developing neurons as well as the effect of miR‐124 on the expression of PTB and nPTB, in order to better understand the role of microRNAs in controlling alternative splicing specifically, and in gene expression in general. Funding provided by NIH and HHMI grants (DLB) and a Warsaw Family Fellowship (PLB).