Emerging Role of MicroRNAs in Reproductive Medicine

Early during summer 2007, I was asked by Dr. Carr to serve as the guest editor for an issue of Seminars in Reproductive Medicine. Selection of a topic relevant to my field of research that would be of interest to general readers of the journal was rather challenging considering the many outstanding articles that were published in previous issues of the journal in past years. However, I became quite convinced that the subject of microRNA (miRNA) in reproduction would be ideal because it has emerged as one of the most active research topics in various fields of biology and medicine in recent years. Comparatively, the miRNA-related research in reproductive biology and medicine is in its early stage of development but will undoubtedly evolve through in-depth investigations. These highly conserved, small, non–protein-coding RNAs have emerged as key regulators of translational efficiency of their complementary target messenger RNAs (mRNAs) from plants to viruses, nematodes, fruit flies, and animals, including humans. In this issue of Seminars in Reproductive Medicine, several articles present evidence regarding the implication of the regulatory function of miRNAs in pituitary, ovarian, uterine, and breast gene expression under normal and pathologic conditions. During the past decade, large-scale gene expression microarray has generated comprehensive information reflecting the molecular signature of various cells and tissues under normal and disease conditions. Although the acquisition of such large genomic data has been highly informative, it has also created the challenge of how to integrate such knowledge to sort out the individual and interactive mechanisms that regulate the expression of these transcripts resulting in implementation of their appropriate biological functions. Despite considerable progress, the significance of the expression of a large number of these transcripts remains unknown, and because of their diversity, predicting their biological relevance has become more complex than was originally envisioned. Adding to this complexity was the recent discovery of miRNAs and their emergence as one of the major components of the individual and interactive mechanisms that regulate gene expression. Since the cloning of the first miRNA, lin-4, in Caenorhabditis elegans a decade ago, several hundred more miRNAs have been identified in various species, including human. Genomic analysis revealed that the genes encoding miRNAs are scattered in all chromosomes except the Y chromosome and are estimated to constitute 1 to 4% of all known genes in higher organisms. In addition, 50% of the miRNA genes are found in clusters and, due to a high degree of relatedness among them in each cluster, they may have derived from gene duplication. Nearly all the miRNAs identified are conserved in closely related species, or many have homologs in distant species, implying their conserved functions throughout evolution. The primary miRNA transcripts, or pri-miRNAs, are several kilobases long and undergo substantial processing resulting in the generation of a small, 70to 90-nucleotide (nt) stem-loop precursor miRNA (pre-miRNA) in the nucleus. The pre-miRNAs are transported into the cytoplasm, where they undergo a second cleavage by the cytoplasmic RNase III, Dicer, generating a doublestranded miRNA duplex. The double-stranded miRNA duplex unwinds and forms a single-strand, mature miRNA that incorporates into the RNAinduced silencing complex (RISC) and through complementary interactions with target genes regulates gene expression mostly but not always through translational repression. Nasser Chegini, Ph.D.