Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5

Markus Maerker, Maike Getwan, Megan E. Dowdle, Jason C. McSheene, Vanessa Gonzalez, José L. Pelliccia, Danielle S. Hamilton, Valeria Yartseva, Charles Vejnar, Melanie Tingler, Katsura Minegishi, Philipp Vick, Antonio J. Giraldez, Hiroshi Hamada, Rebecca D. Burdine, Michael D. Sheets, Martin Blum and Axel Schweickert ()
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Markus Maerker: University of Hohenheim, Institute of Biology, Department of Zoology
Maike Getwan: University of Zurich, Institute of Anatomy
Megan E. Dowdle: University of Wisconsin
Jason C. McSheene: Princeton University
Vanessa Gonzalez: Princeton University
José L. Pelliccia: Princeton University
Danielle S. Hamilton: Princeton University
Valeria Yartseva: Yale University School of Medicine
Charles Vejnar: Yale University School of Medicine
Melanie Tingler: University of Hohenheim, Institute of Biology, Department of Zoology
Katsura Minegishi: Laboratory for Organismal Patterning, RIKEN Center for Biosystems Dynamics Research
Philipp Vick: University of Hohenheim, Institute of Biology, Department of Zoology
Antonio J. Giraldez: Yale University School of Medicine
Hiroshi Hamada: Laboratory for Organismal Patterning, RIKEN Center for Biosystems Dynamics Research
Rebecca D. Burdine: Princeton University
Michael D. Sheets: University of Wisconsin
Martin Blum: University of Hohenheim, Institute of Biology, Department of Zoology
Axel Schweickert: University of Hohenheim, Institute of Biology, Department of Zoology

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Rotating cilia at the vertebrate left-right organizer (LRO) generate an asymmetric leftward flow, which is sensed by cells at the left LRO margin. Ciliary activity of the calcium channel Pkd2 is crucial for flow sensing. How this flow signal is further processed and relayed to the laterality-determining Nodal cascade in the left lateral plate mesoderm (LPM) is largely unknown. We previously showed that flow down-regulates mRNA expression of the Nodal inhibitor Dand5 in left sensory cells. De-repression of the co-expressed Nodal, complexed with the TGFß growth factor Gdf3, drives LPM Nodal cascade induction. Here, we show that post-transcriptional repression of dand5 is a central process in symmetry breaking of Xenopus, zebrafish and mouse. The RNA binding protein Bicc1 was identified as a post-transcriptional regulator of dand5 and gdf3 via their 3′-UTRs. Two distinct Bicc1 functions on dand5 mRNA were observed at pre- and post-flow stages, affecting mRNA stability or flow induced translational inhibition, respectively. To repress dand5, Bicc1 co-operates with Dicer1, placing both proteins in the process of flow sensing. Intriguingly, Bicc1 mediated translational repression of a dand5 3′-UTR mRNA reporter was responsive to pkd2, suggesting that a flow induced Pkd2 signal triggers Bicc1 mediated dand5 inhibition during symmetry breakage.

Date: 2021
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DOI: 10.1038/s41467-021-25464-z

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