Research Interests

Increasingly detailed analysis of vertebrate genomes has shown that the majority of the genome is transcribed into RNA but only a small fraction of the total RNA codes for protein. A much larger fraction consists of noncoding RNAs, both large and small. Broadly, we seek to understand the role that small noncoding RNAs play during vertebrate development focusing mostly on microRNAs (miRNAs). These small RNAs primarily regulate gene expression at the post-transcriptional level via base pairing with specific mRNA targets. Because the pairing is imperfect, the challenge is to identify bona fide mRNA targets. We use zebrafish and mammalian cell lines as model systems to understand the role that miRNAs play during development and disease progression focusing on the following questions:

1. Regulation of Retinal Regeneration
Zebrafish are remarkable in their ability to repair and regenerate damaged tissues including hearts, retinas, nerves, and fins. We previously showed that miRNAs regulate caudal fin regeneration and based on those studies have expanded to examine the regulation of gene expression that occurs during retinal regeneration. The retina is a beautiful tissue with clearly defined, patterned cell types including rods, cones, and Müller glial cells. In humans, loss of rods and cones is largely irreversible but fish are able to recover eyesight even after loss of most rods and cones. Using next generation sequencing technologies, we have identified differentially expressed miRNAs and mRNAs and now seek to experimentally test the role of specific genes and regulatory networks that control retinal regeneration.

2. miRNA Function During Early Vertebrate Development
We have used microarray analyses and next generation sequencing technologies to determine the expression patterns of nearly all zebrafish miRNAs during the first 5 days of development. Using gain- and loss-of-function experiments, we have uncovered a role for miRNA regulation controlling muscle development, the response to osmotic stress, planar cell polarity, synaptic function, vesicular exocytosis, pectoral fin growth, left-right asymmetry, endoderm formation, fin regeneration, and eye development. miRNAs typically regulate a number of mRNAs but when examined at specific times and locations, they control key developmental decisions. Broadly, we would like to know the targets of every single miRNA.

3. Biogenesis and function of extracellular RNAs in cancer
There is increasing evidence that in cancer the secretion of extracellular vesicles, such as exosomes, can manipulate the local and systemic environment to enhance tumor growth and dissemination. Several studies have shown that exosomes contain distinct cargo, including microRNAs (miRNAs), and that they are involved in intercellular communication. An outstanding question regarding extracellular RNAs is whether their export from cells is specific and actively regulated; and if so, how this selection process occurs. Additionally, little is understood about the exact function of extracellular miRNAs and how they pertain to health and disease. Using colon cancer cell lines, we are interested in understanding the biogenesis and function of exosomal miRNAs, the molecular pathway(s) by which miRNAs are sorted to exosomes, and ultimately, how these processes are deregulated during oncogenesis.