Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex

Minegishi, Katsura; Rothé, Benjamin; Komatsu, Kaoru R.; Ono, Hiroki; Ikawa, Yayoi; Nishimura, Hiromi; Katoh, Takanobu A.; Kajikawa, Eriko; Sai, Xiaorei; Miyashita, Emi; Takaoka, Katsuyoshi; Bando, Kana; Kanazawa, Hiroshi; Yamamoto, Tadashi; Saito, Hirohide; Hamada, Hiroshi

doi:10.1038/s41467-021-24295-2

Cited by 36 publications

(66 citation statements)

References 50 publications

(75 reference statements)

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“…5D ). (4) The accompanying manuscript by Minegishi et al 44 demonstrates Bicc1 binding to the mouse Dand5 3′-UTR and identified specific binding motifs. Intriguingly, we found alike sequences in the Bicc1RE, which apparently were located within dS-tpMO or next to dL-tpMO target sequences that specifically impair translational repression in Xenopus (Figure S1B ).…”

Section: Discussionmentioning

confidence: 99%

“…Our work, together with complementing analyses in the mouse (cf. 44 ), constitutes a conceptual advance in our understanding of symmetry breaking, namely the flow-dependent activation of the RNA-binding protein Bicc1 to repress dand5 translation on the left LRO margin in a Dicer-dependent manner. Based on our analyses, we suggest a model schematically depicted in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse and Xenopus , a proximal element of the dand5 3′-UTR is required and sufficient for flow-mediated mRNA decay and translational inhibition, respectively, which is dependent on Bicc1 and Dicer (cf. 44 ). Whether or not miRs are involved in Dicer1-mediated dand5 repression remains open.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…2a, b; Supplementary Video 4): one to visualize perinodal immotile cilia, and the other to monitor the response to mechanical stimuli. Dand5 mRNA is the ultimate target of nodal flow 15, 16 , being degraded by the Bicc1-Ccr4 complex in response to the flow 17 . Crown cells were labeled with the NDE4-hsp-dsVenus-Dand5-3′-UTR transgene, with the level of dsVenus mRNA reflecting that of Dand5 mRNA 17 , whereas their immotile cilia were visualized with a transgene encoding mCherry.…”

Section: Mechanical Stimuli Administered To Immotile Cilia By Optical...mentioning

confidence: 99%

Immotile cilia of the mouse node sense a fluid flow–induced mechanical force for left-right symmetry breaking

Katoh

Omori

Mizuno

et al. 2022

Preprint

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Immotile cilia of crown cells at the node of mouse embryos are required for sensing of a leftward fluid flow1 that gives rise to the breaking of left–right (L–R) symmetry2. The flow–sensing mechanism has long remained elusive, however, with both mechanosensing and chemosensing models having been proposed1,3–5. Here we show that immotile cilia at the mouse node respond to mechanical force. In the presence of a leftward flow, immotile cilia on the left side of the node bend toward the ventral side whereas those on the right side bend toward the dorsal side. Application of mechanical stimuli to immotile cilia along the dorsoventral axis by optical tweezers induced Ca2+ transients and degradation of Dand5 mRNA–the first known L–R asymmetric molecular events–in the targeted cells. The Pkd2 channel protein was found to be preferentially localized to the dorsal side of immotile cilia on both left and right sides of the node, and the observed induction of Ca2+ transients preferentially by mechanical stimuli directed toward the ventral side could explain the differential response of immotile cilia to the directional flow. Our results thus suggest that immotile cilia at the node sense the direction of fluid flow in a manner dependent on a flow–generated mechanical force.

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“…To establish transgenic lines in which KV-epithelial cells are specifically labelled, we cloned the 5-kb upstream sequence of zebrafish dand5 (Figure 1b). A previous transient promoter assay demonstrated that the upstream sequence of zebrafish dand5 drives the reporter expression around KV (Gourronc et al, 2007), but stable transgenic lines using the dand5 promoter have yet to be estab- This can be explained by the fact that 3' untranslated sequence of mouse dand5 is responsible for its right-sided expression (Minegishi et al, 2021;Nakamura et al, 2012). Untranslated sequences of zebrafish dand5, which are not included in the plasmid construct of this study, could have a similar function to that of mouse dand5.…”

Section: Establishment Of Dand5:egfp To Specifically Label Kv-epithel...mentioning

confidence: 85%

Reemployment of Kupffer’s vesicle cells into axial and paraxial mesoderm via transdifferentiation

et al. 2022

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Kupffer's vesicle (KV) in the teleost embryo is a fluid‐filled vesicle surrounded by a layer of epithelial cells with rotating primary cilia. KV transiently acts as the left‐right organizer and degenerates after the establishment of left‐right asymmetric gene expression. Previous labelling experiments in zebrafish embryos indicated that descendants of KV‐epithelial cells are incorporated into mesodermal tissues after the collapse of KV. However, the overall picture of their differentiation potency had been unclear due to the lack of suitable genetic tools and molecular analyses. In the present study, we established a novel zebrafish transgenic line with a promoter of dand5, in which all KV‐epithelial cells and their descendants are specifically labelled until the larval stage. We found that KV‐epithelial cells undergo epithelial‐mesenchymal transition upon KV collapse and infiltrate into adjacent mesodermal progenitors, the presomitic mesoderm and chordoneural hinge. Once incorporated, the descendants of KV‐epithelial cells expressed distinct mesodermal differentiation markers and contributed to the mature populations such as the axial muscles and notochordal sheath through normal developmental process. These results indicate that differentiated KV‐epithelial cells possess unique plasticity in that they are reemployed into mesodermal lineages through transdifferentiation after they complete their initial role in KV.

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Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex

Cited by 36 publications

References 50 publications

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

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

Immotile cilia of the mouse node sense a fluid flow–induced mechanical force for left-right symmetry breaking

Reemployment of Kupffer’s vesicle cells into axial and paraxial mesoderm via transdifferentiation

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