Nuclear Hormone Receptor Regulation of MicroRNAs Controls Developmental Progression

• Published in: Science (American Association for the Advancement of Science) 2009-04, Vol.324 (5923), p.95-98
• Main Authors: Bethke, Axel, Fielenbach, Nicole, Wang, Zhu, Mangelsdorf, David J, Antebi, Adam
• Format: Article
• Language: English
• Subjects: Aging; Animals; Animals, Genetically Modified; Biological and medical sciences; Caenorhabditis elegans; Caenorhabditis elegans - cytology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cell receptors; Cell structures and functions; Cellular biology; Cholestenes - metabolism; Daughter cells; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Fundamental and applied biological sciences. Psychology; Gene expression; Gene expression regulation; Gene Expression Regulation, Developmental; Genes, Helminth; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Humans; Larval development; Ligands; MicroRNA; MicroRNAs - genetics; Molecular and cellular biology; Molecular biology; Mutation; Nematode larvae; Pharynx; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Repression; Response Elements; Ribonucleic acid; RNA; RNA, Helminth - genetics; RNA, Helminth - metabolism; Signal Transduction; Stem cells; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Up-Regulation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1164899

In response to small-molecule signals such as retinoids or steroids, nuclear receptors activate gene expression to regulate development in different tissues. MicroRNAs turn off target gene expression within cells by binding complementary regions in messenger RNA transcripts, and they have been broadly implicated in development and disease. Here we show that the Caenorhabditis elegans nuclear receptor DAF-12 and its steroidal ligand directly activate promoters of let-7 microRNA family members to down-regulate the microRNA target hbl-1, which drives progression of epidermal stem cells from second to third larval stage patterns of cell division. Conversely, the receptor without the ligand represses microRNA expression during developmental arrest. These findings identify microRNAs as components of a hormone-coupled molecular switch that shuts off earlier developmental programs to allow for later ones.