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Correct specification of the left-right (L-R) axis is important for organ morphogenesis. Conserved mechanisms involving cilia rotation inside node-like structures and asymmetric Nodal signaling in the lateral plate mesoderm (LPM), which are important symmetry-breaking events, have been intensively studied. In zebrafish, the clustering and migration of dorsal forerunner cells (DFCs) is critical for the formation of the Kuppfer's vesicle (KV). However, molecular events underlying DFC clustering and migration are less understood. The WD-repeat proteins function in a variety of biological processes, including cytoskeleton assembly, intracellular trafficking, mRNA splicing, transcriptional regulation and cell migration. However, little is known about the function of WD-repeat proteins in L-R asymmetry determination. Here, we report the identification and functional analyses of zebrafish  wdr18 , a novel gene that encodes a WD-repeat protein that is highly conserved among vertebrate species.  wdr18  was identified from a  Tol2  transposon-mediated enhancer trap screen. Follow-up analysis of  wdr18  mRNA expression showed that it was detected in DFCs or the KV progenitor cells and later in the KV at early somitogenesis stages. Morpholino knockdown of  wdr18  resulted in laterality defects in the visceral organs, which were preceded by the mis-expression of Nodal-related genes, including  spaw  and  pitx2 . Examination of morphants at earlier stages revealed that the KV had fewer and shorter cilia which are immotile and a smaller cavity. We further investigated the organization of DFCs in  wdr18  morphant embryos using  ntl  and  sox17  as specific markers and found that the clustering and migration of DFC was altered, leading to a disorganized KV. Finally, through a combination of  wdr18  and  itgb1b  morpholino injections, we provided evidence that  wdr18  and  itgb1b  genetically interact in the laterality determination process. Thus, we reveal a new and essential role for WD-repeat proteins in the determination and regulation of L-R asymmetry and propose a potential mechanism for  wdr18  in the regulation of DFC clustering and migration and KV formation.

Wdr18 Is Required for Kupffer's Vesicle Formation and Regulation of Body Asymmetry in Zebrafish