Abstract
Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand5 mRNA on the left side. We here examined how the fluid flow induces Dand5 mRNA decay. We found that the first 200 nucleotides in the 3′ untranslated region (3′-UTR) of Dand5 mRNA are necessary and sufficient for the left-sided decay and to mediate the response of a 3′-UTR reporter transgene to Ca2+, the cation channel Pkd2, the RNA-binding protein Bicc1 and their regulation by the flow direction. We show that Bicc1 preferentially recognizes GACR and YGAC sequences, which can explain the specific binding to a conserved GACGUGAC motif located in the proximal Dand5 3′-UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node. These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc1 and Ccr4-Not to mediate Dand5 mRNA degradation specifically on the left side of the node.
Highlights
Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand[5] mRNA on the left side
We have identified an element in the 3′ untranslated region (3′-UTR) of Dand[5] mRNA that is responsible for the asymmetric decay of this mRNA at the node of the mouse embryo in a manner dependent on Bicc[1] and the Ccr4-Not subunit Cnot[3]
To test whether the NDEHsp-destabilized Venus (dsVenus)-3′-UTR transgene is regulated by nodal flow, we introduced it into iv/iv (Dnah11iv/iv) mutant embryos, which lack the fluid flow[19]
Summary
Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand[5] mRNA on the left side. The Cnot[3] component of the Ccr4-Not deadenylase complex interacts with Bicc[1] and is required for Dand[5] mRNA decay at the node These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc[1] and Ccr4-Not to mediate Dand[5] mRNA degradation on the left side of the node. We have identified an element in the 3′ untranslated region (3′-UTR) of Dand[5] mRNA that is responsible for the asymmetric decay of this mRNA at the node of the mouse embryo in a manner dependent on Bicc[1] and the Ccr4-Not subunit Cnot[3]
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