title: The nodal inhibitor Coco is a critical target of leftward flow in Xenopus.
abstract: Vertebrate laterality, which is manifested by asymmetrically placed organs [1], depends on asymmetric activation of the Nodal signaling cascade in the left lateral plate mesoderm [2]. In fish, amphibians, and mammals, a cilia-driven leftward flow of extracellular fluid acts upstream of the Nodal cascade [3-6]. The direct target of flow has remained elusive. In Xenopus, flow occurs at the gastrocoel roof plate (GRP) in the dorsal midline of the embryo [4, 7]. The GRP is bordered by a second, bilaterally symmetrical Nodal expression domain [8]. Here we identify the Nodal inhibitor Coco as a critical target of flow. Coco and Xenopus Nodal-related 1 (Xnr1) are coexpressed in the lateralmost ciliated GRP cells. Coco becomes downregulated on the left side of the GRP as a direct readout of flow. Ablation of flow prevented Coco repression, whereas Xnr1 expression was independent of flow. Loss of flow-induced laterality defects were rescued by knockdown of Coco on the left side. Parallel knockdown of Coco and Xnr1 in GRP cells restored laterality defects in flow-impaired embryos, demonstrating that Coco acted through GRP-expressed Xnr1. Coco thus acts as a critical target of flow, suggesting that symmetry is broken by flow-mediated left-asymmetric release of Nodal repression at the midline.
authors.affiliation: Institute of Zoology, University of Hohenheim, D-70593 Stuttgart, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schweickert
authors.forename: Philipp
authors.initials: P
authors.lastname: Vick
authors.forename: Maike
authors.initials: M
authors.lastname: Getwan
authors.forename: Thomas
authors.initials: T
authors.lastname: Weber
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schneider
authors.forename: Melanie
authors.initials: M
authors.lastname: Eberhardt
authors.forename: Tina
authors.initials: T
authors.lastname: Beyer
authors.forename: Anke
authors.initials: A
authors.lastname: Pachur
authors.forename: Martin
authors.initials: M
authors.lastname: Blum
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000502:physiology; D004627:Embryonic Induction; D009024:Morphogenesis / Q000502:physiology*; D055457:Nodal Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000033:anatomy & histology* / Q000196:embryology*
chemical_list: C473314:DAND5 protein, Xenopus; D055457:Nodal Protein; D029867:Xenopus Proteins; C512833:nodal1 protein, Xenopus