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

Nat Cell Biol. 2011 Aug 21;13(9):1062-9. doi: 10.1038/ncb2316.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Feedback, Physiological
  • Female
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Immunohistochemistry
  • Janus Kinases / genetics
  • Janus Kinases / metabolism*
  • Male
  • MicroRNAs / genetics*
  • Microscopy, Confocal
  • Models, Biological
  • Mutation
  • Oocytes / cytology
  • Oocytes / metabolism
  • Ovary / cytology
  • Ovary / metabolism
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Ken protein, Drosophila
  • MIRN279 microRNA, Drosophila
  • MicroRNAs
  • STAT Transcription Factors
  • Transcription Factors
  • apt protein, Drosophila
  • Green Fluorescent Proteins
  • Janus Kinases
  • hop protein, Drosophila