TY - JOUR
T1 - Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5
AU - Maerker, Markus
AU - Getwan, Maike
AU - Dowdle, Megan E.
AU - McSheene, Jason C.
AU - Gonzalez, Vanessa
AU - Pelliccia, José L.
AU - Hamilton, Danielle S.
AU - Yartseva, Valeria
AU - Vejnar, Charles
AU - Tingler, Melanie
AU - Minegishi, Katsura
AU - Vick, Philipp
AU - Giraldez, Antonio J.
AU - Hamada, Hiroshi
AU - Burdine, Rebecca D.
AU - Sheets, Michael D.
AU - Blum, Martin
AU - Schweickert, Axel
N1 - Funding Information:
We thank M. Montino for performing initial Bicc1 experiments in Xenopus during his diploma thesis. Technical assistance was given by E. Schuster. S. Mai helped with critical proofreading. O. Wessely provided the full-length mouse bicc1 construct. We thank H. Sasaki for NotoCreERT2 mice and Philip Johnson for zebrafish husbandry. M.G. was the recipient of a Ph.D. fellowship from the Landesgraduiertenförderung Baden-Württemberg. Work in the Blum lab was supported by DFG grant BL285/9-2. Work in the Sheets lab was supported by the National Institute of Child Health and Human Development of the National Institutes of Health under award number R01HD091921. Work in the Hamada lab was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (no. 17H01435) and from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (no. JPMJCR13W5) to H.H.; by a Grant-in-Aid (No. 18K14725) for Early-Career Scientists from the Japan Society for the Promotion of Science (JSPS), a Kakehashi grant from BDR-Otsuka Pharmaceutical Collaboration Center, and a research grant (no. 2018M-018) from the Kato Memorial Bioscience Foundation to K.M. Work in the Giraldez lab was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM12258003. Work in the Burdine lab was supported by the National Institute of Child Health and Human Development of the National Institutes of Health under grant number T32GM007388, and a United Negro College Fund/Merck Graduate Science Research Dissertation Fellowship to JCM. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-25464-z
DO - 10.1038/s41467-021-25464-z
M3 - Article
C2 - 34531379
AN - SCOPUS:85115292754
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5482
ER -