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First published online 3 May 2006
doi: 10.1242/dev.02384

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The left-right axis in the mouse: from origin to morphology

Developmental Genetics Group, Graduate School for Frontier Biosciences, Osaka University, and CREST, Japan Science and Technology Corporation (JST), 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.

View larger version (37K): [in a new window]   Fig. 1. Mechanisms of left-right (LR) patterning in mouse embryo. (A) Three steps in the generation of LR asymmetry: a symmetry-breaking event in the node, the patterning of the lateral plate mesoderm (LPM) and asymmetric organogenesis. The black arrow on the left represents a time course during development, from earlier embryonic (E7.5) stages to later ones (E10-11.5). (B) Posterior view of a mouse embryo at E8.0 showing Nodal expression in the node and left LPM. (C) A transverse section taken at the level indicated by the red lines in B. The location of pit cells, crown cells, paraxial mesoderm (PAM), LPM, endoderm and prospective floor plate are shown. Arrows indicate how signals are transferred during LR patterning. Asymmetric signal(s) generated by the leftward flow in the node (black wavy lines) might be transferred to the left LPM, either through the endoderm (pink line) or through the PAM (red line). According to the determinant-transporting model, an unknown molecule produced in the node/perinodal cells is secreted into the node cavity and transported towards the left side, where its signal may be transduced by the endoderm and finally by the LPM (pink line). Alternatively, cells in or near the node may sense the mechanical stress and send an unknown signal(s) to the left LPM thorough the PAM (red line). It is also possible that the perinodal (crown) cells respond to the chemical determinant and send a signal via the red route.

View larger version (144K): [in a new window]   Fig. 2. Leftward fluid flow generated by rotational movement of node cilia. (A) Lateral view of a mouse embryo at 8.0 dpc. Scale bar: 100 µm. (B) Monocilia in the node of a mouse embryo shown at high magnification. Scale bar: 1 µm. (C) Ventral view of the node cavity. Anteroposterior (AP) and left-right (LR) orientations are indicated. Red arrow indicates the direction of nodal flow. Scale bar: 10 µm. (D) Ventral view of the node cavity, with fluorescent beads used to visualize fluid flow. The beads move towards the left side of the node (arrow). Scale bar: 10 µm. Image in D courtesy of Shigenori Nonaka (National Institute for Basic Biology, Japan).

View larger version (15K): [in a new window]   Fig. 3. De novo generation of left-right (LR) asymmetry via three sources of positional information. Node pit cells of E8.0 mouse embryo are illustrated. Each cilium (red bar) protrudes from a node pit cell (light blue) towards the ventral side of the mouse embryo. The cilium is also posteriorly tilted, most probably because the position of the basal body (green) is posteriorly shifted within each cell. Each cilium rotates in a clockwise direction when viewed from the ventral side. The posterior tilt of the ciliary rotation axis generates a leftwards flow instead of a vortex. LR asymmetry is thus formed de novo through a combination of dorsoventral information, anteroposterior information and the unidirectionality of ciliary rotation.

View larger version (19K): [in a new window]   Fig. 4. Two models for the mechanism of action of nodal flow. (A) The transportation of a left-right (LR) determinant or (B) the generation and sensing of mechanical stress by leftward flow at cilia. Modified, with permission, from Nonaka et al. (Nonaka et al., 1998).

View larger version (25K): [in a new window]   Fig. 5. Genetic pathway for, and signal transfer during, left-right (LR) patterning. (A) A genetic pathway for LR patterning. Only major components are shown. An asymmetric signal generated in the node initiates Nodal-Lefty1-Lefty2 regulatory loops in the left lateral plate mesoderm (LPM). Nodal activity induces Pitx2 expression in the left LPM. The broken line represents the midline. Lrd and Inv are required to generate asymmetric signal in the node. Foxh1 is a component of the Nodal-Lefty loops. (B) Signal transfer during LR patterning. A ventral view of an E8.0 mouse embryo. At least four steps of signal transfer take place during LR patterning: (1) from the node to the left LPM; (2) within the LPM; (3) from the left and right LPM to the midline; and (4) from the midline to the LPM. The Nodal signal is transferred in the second and third steps, but the identity of the signal that is transferred from the node to the LPM is unknown. In the fourth step, a midline signal (Lefty1) negatively regulates Nodal in the LPM. Pink arrow, the nodal flow; pink oval, a small region of LPM that initially receives the signal from the node. The expression domains of Nodal (red), and Lefty1 and Lefty2 (blue) are indicated.

View larger version (66K): [in a new window]   Fig. 6. Dynamic expression pattern of Nodal. (A,B) Ventral (A) and posterior (B) views of mouse embryos. (A) Nodal expression begins in the node at E7.5 and (B) develops asymmetrically a few hours later (four-somite stage) in the lateral plate mesoderm (LPM). (C-E) Lateral views of mouse embryos. (C) Nodal expression in the left LPM begins in a small region at the level of the node (purple arrow) at the two- to three-somite (s) stage at E8.0. (D) It then expands rapidly within the left LPM along the AP axis (red arrows indicate the expansion of Nodal expression), and (E) disappears by the seven-somite stage (red arrow indicates). Figure courtesy of Chikara Meno (Kyushu University, Japan).

View larger version (19K): [in a new window]   Fig. 7. Two steps in the generation of robust left-right (LR) asymmetry in the lateral plate mesoderm (LPM). In this model, robust LR asymmetry (asymmetric Nodal expression) in the LPM is generated in two steps. (A,B) First, nodal flow generates a small difference (pink) between the two sides of the LPM. (C) This small difference is then converted to a robust asymmetry by a reaction-diffusion (RD) system comprising Nodal and Lefty proteins. (D) Photomicrograph illustrating this asymmetry. A RD system requires that both an activator and inhibitor travel over a long distance and that an inhibitor diffuses faster than an activator does. Circumstantial evidence supports that Nodal and Lefty fulfill these requirements (Chen and Schier, 2001; Chen and Schier, 2002; Meno et al., 2001; Sakuma et al., 2002).

View larger version (34K): [in a new window]   Fig. 8. Generation of anatomical asymmetries. (A-C) Three different mechanisms for the generation of morphological asymmetries: (A) directional looping, (B) differential branching and (C) one-sided regression. Examples of anatomical structures generated by each mechanism are shown. Figure courtesy of Yukio Saijoh (University of Utah, USA).