Sequential and additive expression of miR-9 precursors control timing of neurogenesis

Ximena Soto*, Joshua Burton, Cerys S. Manning, Thomas Minchington, Robert Lea, Jessica Lee, Jochen Kursawe, Magnus Rattray, Nancy Papalopulu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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MicroRNAs (miRs) have an important role in tuning dynamic gene expression. However, the mechanism by which they are quantitatively controlled is unknown. We show that the amount of mature miR-9, a key regulator of neuronal development, increases during zebrafish neurogenesis in a sharp stepwise manner. We characterize the spatiotemporal profile of seven distinct microRNA primary transcripts (pri-mir)-9s that produce the same mature miR-9 and show that they are sequentially expressed during hindbrain neurogenesis. Expression of late-onset pri-mir-9-1 is added on to, rather than replacing, the expression of early onset pri-mir-9-4 and -9-5 in single cells. CRISPR/Cas9 mutation of the late-onset pri-mir-9-1 prevents the developmental increase of mature miR-9, reduces late neuronal differentiation and fails to downregulate Her6 at late stages. Mathematical modelling shows that an adaptive network containing Her6 is insensitive to linear increases in miR-9 but responds to stepwise increases of miR-9. We suggest that a sharp stepwise increase of mature miR-9 is created by sequential and additive temporal activation of distinct loci. This may be a strategy to overcome adaptation and facilitate a transition of Her6 to a new dynamic regime or steady state.
Original languageEnglish
Article numberdev200474
Number of pages14
Issue number19
Publication statusPublished - 1 Oct 2022


  • pri-mir-9
  • miR-9
  • Neurogenesis
  • Zebrafish
  • Temporal control


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