Co-authors (L to R): Philip S. Choi, Catherine Dulac, Alexander F. Schier, Wen-Yee Choi, Lisa Zakhary, and Sophie Caron
Modern genetics textbooks highlight the concept of the ‘central dogma’ which states that DNA is transcribed into messenger RNA (mRNA) and that mRNA is subsequently translated into proteins. Yet, only a small fraction (~2-3%) of these mRNAs actually encodes proteins in higher eukaryotes. What do the rest of the mRNAs do? It is becoming increasingly appreciated that many of these mRNAs comprise non-coding RNA that play critical roles as gene regulators. One specific class of non-coding RNAs is called microRNAs (miRNAs), which, as the name suggests, are short ~22-26 nucleotide RNAs that regulate gene expression by directing degradation and/or preventing translation of protein encoding mRNAs. It is widely believed that higher vertebrates like human and mice harbor 400-500 genomic miRNAs which act either alone or in combination to regulate ~30% of their genes and to control such varied processes as heart formation, stem cell division, and lung development. Which miRNAs act on which target genes to affect which developmental processes?
Our lab has been interested in understanding the mechanisms that regulate development of olfactory sensory neurons (OSNs), which are the cells that detect odorants in the environment. While most research in the field has focused on protein regulators of genes called transcription factors, we wondered whether non-coding RNAs might play an important role. Now, in a study published in Neuron (Choi et al., 2008), we show that at least 90 miRNAs are expressed in the olfactory system of mice and that the miR-200 family of miRNAs is particularly important for development of progenitor cells into OSNs.
Initially, we were intrigued that no abnormal phenotypes arose when we eliminated the function of those miRNAs expressed in mature OSNs. However, eliminating the function of those miRNAs expressed in OSN progenitor cells prevented OSN maturation, resulting in cell death and indicating that miRNAs are specifically required for olfactory neurogenesis. We then took advantage of zebrafish, which allowed us to eliminate the function of individual miRNAs within an olfactory system that is remarkably conserved relative to mice. Inhibition of a single family (miR-200) of miRNAs, which we show to be specifically expressed in OSN progenitor cells, prevented development into mature OSNs, indicating that a single miRNA family is critically important for olfactory neurogenesis.
We are currently working to elucidate the targets through which the miR-200 family acts in this process and to further the zebrafish model as a platform for dissecting the functions of other interesting olfactory-expressed miRNAs. In the meantime, we hope that genetics textbooks will be updated to reflect the outsized role that small, non-coding RNAs play in developmental biology.