Fig. 6

Multiple genetic pathways control the formation and function of Kupffer′s vesicle to direct LR development. We propose five steps (1-5) that are required to set up normal asymmetric expression patterns of Nodal, Lefty and Pitx2 gene family members and subsequent morphological asymmetry of the heart, brain and gut in the zebrafish embryo. First, DFCs are specified during the blastula period. Probably among a number of yet unidentified factors, cas is required for proper DFC formation. Second, the ntl and oep (Nodal signaling) pathways control the expression of Left-Right dynein (lrdr1), a ciliary motor protein, in DFCs. Third, DFCs organize to form KV during early somitogenesis. ntl and oep are also essential for this step. By contrast, spt is required for KV organogenesis but not for lrdr1 expression in DFCs. Fourth, cilia assemble on cells lining the fluid-filled lumen of KV. Fifth, KV cilia become motile, which is dependent on left-right dynein, and generate a directional flow of fluid inside KV. We suggest that fluid flow inside KV, a transient embryonic organ of asymmetry, initiates asymmetric gene expression in lateral tissue that leads to normal LR development.