The problem of how the regulation of specific targets contributes to the functional repertoire of individual microRNAs (miRNAs) during development and disease is a central question in developmental biology. Recent studies have demonstrated that miRNAs promote the repression of their targets in the context of a single cell. miR-1/206 is a muscle-specific miRNA and is responsible for the regulation of >54% target mRNAs during muscle development in zebrafish. However, loss of miR-1/206 function in somites also results in increased growth and proliferation in the surrounding segmental arteries. This presents the intriguing possibility that miRNAs may play a role in modulating cross-talk between tissues. Sequence analysis of muscle-expressed genes involved in angiogenesis revealed that VEGF-A is a potential miR-1/206 target and that this regulation is conserved among vertebrates. The goal of this project is therefore to understand how individual miRNA/target interactions regulate gene expression during vertebrate development by: 1) Establishing the role of miR-1/206 in vascular development in vivo. 2) Studying miR-1/206 dependent regulation of vegfA genes. 3) Testing the physiological relevance of individual miRNA/target interactions in the context of miR-1/206 and VEGF-A signaling during vascular development. In better understanding how miRNA/target interactions regulate signaling pathways during development, we will gain insight how these interactions contribute to normal development as well as how dysregulation of this interaction may contribute to human disorders and diseases.
A pivotal step in tumor progression and metastasis is the invasion or co-option of normal capillaries and their proliferation in tumors. Because the signaling mechanisms are shared between normal development and the pathological state, the study of embryonic blood vessel development is of great relevance. In addition, up-regulation of VEGF in humans leads to age-related macular degeneration and diabetic retinopathy. This study has the potential to provide fundamental insights into the role miRNAs play in human diseases, tumor angiogenesis and cancer metastasis.
