Asymmetric repression of the Nodal inhibitor Coco by cilia-driven leftward flow in Xenopus

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A cilia-driven flow of extracellular fluid breaks the bilateral symmetry of the early neurula frog embryo. In Xenopus, this directional flow from right to left occurs at the so-called gastrocoel roof plate (GRP), an epithelium of mesodermal fate which is transiently embedded in the endodermal layer of the archenteron roof. Leftward flow represents an ancestral character of the vertebrates, although variations do exist. As a consequence of flow, the Nodal signaling cascade becomes asymmetrically activated in the left lateral plate mesoderm (LPM). This cascade then directs the asymmetric morphogenesis of inner organs such as the heart. Our preliminary experiments identify for the first time the critical target of flow: the Nodal inhibitor Coco, which becomes down-regulated at the mRNA and protein level on the left margin of the GRP and thus lifts repression of the coexpressed Nodal protein. Epistasis experiments show that Nodal and Coco act downstream of flow, and Nodal downstream of Coco. This proposal addresses the question how flow achieves this repression. The problem is addressed from two sides: (1) analysis of the input of flow, and (2) investigation of the regulation of Coco mRNA and protein levels. The latter will be investigated on the basis of the two currently discussed models, namely that (2a) a morphogen is transported to the left side, or that (2b) sensory cilia at the left margin receive and process the directionality of flow. Our goal is to unravel the mechanism of flow-driven release of Coco-mediated repression of Nodal on the left side of the GRP.