Cilia multifunctional organelles at the center of vertebrate left-right asymmetry.

Abstract

Cilia establish the vertebrate left-right (LR) axis and are integral to the development and function of the kidney, liver, and brain. Left-right asymmetry is established in the ciliated ventral node cells of the mouse. The chiral structure of the cilium provides a reference asymmetry to impose handed LR asymmetric development on the bilaterally symmetric vertebrate embryo. A ciliary mechanism of LR development is evolutionarily conserved, as ciliated organs essential to LR axis formation, called LR organizers, are found in other vertebrates, including rabbit, fish, and Xenopus. Mice with mutations affecting ciliary biogenesis, motility, or sensory function have abnormal LR development and abnormal development of the heart. The axonemal dynein heavy chain left-right dynein (lrd) localizes to the LR organizer and drives counterclockwise movement of node primary cilia. Node primary cilia are an admixture of 9 + 2 and 9 + 0 cilia. Mutations in lrd result in structurally normal, immotile node monocilia. In the mouse, coordinated, directional beating of motile node monocilia at the neural fold stage generates leftward flow of extraembryonic fluid surrounding the node (nodal flow). Nodal flow triggers a rise in intracellular calcium in cells at the left side of the node. The perinodal asymmetric rise in intracellular calcium generated by nodal flow subsequently leads to asymmetric gene expression and morphogenesis.