Cilia in Left-Right Symmetry Breaking

Abstract

Visceral organs of vertebrates show left-right (L-R) asymmetry with regard to their position and morphology. Cilia play essential role in generating L-R asymmetry. A number of genes required for L-R asymmetry have now been identified in vertebrates, including human, many of which contribute to the formation and motility of cilia. In the mouse embryo, breaking of L-R symmetry occurs in the ventral node, where two types of cilia (motile and immotile) are present. Motile cilia are located at the central region of the node, and generate a leftward fluid flow. These motile cilia at the node are unique in that they rotate in the clockwise direction, unlike other immotile cilia such as airway cilia that show planar beating. The second type of cilia essential for L-R asymmetry is immotile cilia that are peripherally located immotile cilia. They sense a flow-dependent signal, which is either chemical or mechanical in nature. Although Ca²⁺ signaling is implicated in flow sensing, the precise mechanism remains unknown.

Figure 1.

Three step for L–R asymmetry. Three steps that contribute to the generation of L–R asymmetry are shown: (1) symmetry breaking, (2) differential patterning of the lateral plate mesoderm (LPM), and (3) asymmetric organogenesis. Scanning microscopic view of node cilia is shown for the symmetry-breaking step, whereas left-sided expression of Nodal and Lefty in the lateral plate is shown for the differential patterning step. For asymmetric organogenesis, three different mechanisms that can give rise to asymmetric anatomical structures are illustrated: differential branching, directional looping, and one-sided regression.

Figure 2.

Node cilia in the E8.0 mouse embryo. Cells harbor one single cilium inside the node cavity in the E8.0 mouse embryo. The length of cilium is between 2 to 6 µm. Scale bar, 10 µm. A, Anterior; P, posterior; L, left; R, right.

Figure 3.

Ultrastructure of mouse motile cilia. (A) Two types of motile cilia in mammals. 9+2 type cilia have one central pair of microtubule and radial spokes at the center of the axoneme, whereas 9+0 type cilia do not contain any central structure. (B) Node cilia basal body. Scale bar, 200 nm. A, A-tubule; B, B-tubule; C, C-tubule.

Figure 4.

Planar cell polarity (PCP) of node cells. The PCP core proteins are localized at the apical membrane of the node cells: Dishevelled is localized at the posterior side of the apical membrane and controls positioning of the node cilia basal body. Scale bar, 2 µm.

Figure 5.

Immotile cilia sense the flow. Two types of cilia found in the node are shown: motile cilia located in the central region of the node generate the flow, while immotile cilia located peripherally (pink) sense the flow. Flow sensing involves a ciliary localized Pkd1l1–Pkd2 complex with Ca²⁺ channel activity. Flow-mediated signals lead to degradation of Cerl2 mRNA. In this model, an immotile cilium on the left side is bent in response to the flow. However, this has not been confirmed in vivo.