title: miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, Center for Cell Dynamics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Suite 450, Baltimore, Maryland 21205, USA.
authors.forename: Wan Hee
authors.initials: WH
authors.lastname: Yoon
authors.forename: Hans
authors.initials: H
authors.lastname: Meinhardt
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Montell
mesh_terms: D000465:Algorithms; D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D008954:Models, Biological; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C508384:Ken protein, Drosophila; C568310:MIRN279 microRNA, Drosophila; D035683:MicroRNAs; D050791:STAT Transcription Factors; D014157:Transcription Factors; C108529:apt protein, Drosophila; D049452:Green Fluorescent Proteins; D053612:Janus Kinases; C085845:hop protein, Drosophila