Dataset Information

Nuclear hormone receptor regulation of microRNAs controls developmental progression.

ABSTRACT: 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.

SUBMITTER: Bethke A

PROVIDER: S-EPMC2757405 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nuclear hormone receptor regulation of microRNAs controls developmental progression.

Bethke Axel A Fielenbach Nicole N Wang Zhu Z Mangelsdorf David J DJ Antebi Adam A

Science (New York, N.Y.) 20090401 5923

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 ...[more]

PMID: 19342589

Similar Datasets

Project description:In insects, precisely timed periodic pulses of the molting hormone ecdysone control major developmental transitions such as molts and metamorphosis. The synthesis and release of ecdysone, a steroid hormone, is itself controlled by PTTH (prothoracicotopic hormone). PTTH transcript levels oscillate with an 8 h rhythm, but its significance regarding the timing of ecdysone pulses is unclear. PTTH acts on its target tissue, the prothoracic gland (PG), by activating the Ras/Raf/ERK pathway through its receptor Torso, however direct targets of this pathway have yet to be identified. Here, we demonstrate that Drosophila Hormone Receptor 4 (DHR4), a nuclear receptor, is a key target of the PTTH pathway and establishes temporal boundaries by terminating ecdysone pulses. Specifically, we show that DHR4 oscillates between the nucleus and cytoplasm of PG cells, and that the protein is absent from PG nuclei at developmental times when low titer ecdysone pulses occur. This oscillatory behavior is blocked when PTTH or torso function is abolished, resulting in nuclear accumulation of DHR4, while hyperactivating the PTTH pathway results in cytoplasmic retention of the protein. Increasing DHR4 levels in the PG can delay or arrest development. In contrast, reducing DHR4 function in the PG triggers accelerated development, which is caused by precocious ecdysone signaling due to a failure to repress ecdysone pulses. Finally, we show that DHR4 negatively regulates the expression of a hitherto uncharacterized cytochrome P450 gene, Cyp6t3. Disruption of Cyp6t3 function causes low ecdysteroid titers and results in heterochronic phenotypes and molting defects, indicating a novel role in the ecdysone biosynthesis pathway. We propose a model whereby nuclear DHR4 controls the duration of ecdysone pulses by negatively regulating ecdysone biosynthesis through repression of Cyp6t3, and that this repressive function is temporarily overturned via the PTTH pathway by removing DHR4 from the nuclear compartment.

Dataset Information

Nuclear hormone receptor regulation of microRNAs controls developmental progression.

Publications

Nuclear hormone receptor regulation of microRNAs controls developmental progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets