miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold.

TitlemiRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold.
Publication TypeJournal Article
Year of Publication2011
AuthorsYoon WHee, Meinhardt H, Montell DJ
JournalNat Cell Biol
Date Published2011 Aug 21
KeywordsAlgorithms, Animals, Animals, Genetically Modified, Cell Line, DNA-Binding Proteins, Drosophila melanogaster, Drosophila Proteins, Feedback, Physiological, Female, Green Fluorescent Proteins, Immunohistochemistry, Janus Kinases, Male, MicroRNAs, Microscopy, Confocal, Models, Biological, Mutation, Oocytes, Ovary, STAT Transcription Factors, Transcription Factors

<p>Patterns of cell fates generated by morphogens are critically important for normal development; however, the mechanisms by which graded morphogen signals are converted into all-or-none cell fate responses are incompletely understood. In the Drosophila ovary, high and sustained levels of the secreted morphogen Unpaired (Upd) specify the migratory border-cell population by activating the signal transducer and activator of transcription (STAT). A lower or transient level of STAT activity specifies a non-migratory population of follicle cells. Here we identify miR-279 as a component of a feedback pathway that further dampens the response in cells with low levels of JAK/STAT activity. miR-279 directly repressed STAT, and loss of miR-279 mimicked STAT gain-of-function or loss of Apontic (Apt), a known feedback inhibitor of STAT. Apt was essential for miR-279 expression in non-migratory follicle cells, whereas another STAT target, Ken and Barbie (Ken), downregulated miR-279 in border cells. Mathematical modelling and simulations of this regulatory circuit including miR-279, Apt and Ken supported key roles for miR-279 and Apt in generating threshold responses to the Upd gradient.</p>

Alternate JournalNat Cell Biol
PubMed ID21857668
PubMed Central IDPMC3167036
Grant ListR01 GM046425 / GM / NIGMS NIH HHS / United States
R01 GM046425-10S1 / GM / NIGMS NIH HHS / United States
GM46425 / GM / NIGMS NIH HHS / United States