|
Fig. 1. Asymmetric organs. In humans, asymmetric organs are found in the chest (heart, lung) and abdomen (stomach, spleen, liver, small and large intestine). The apex of the heart, which is placed at the midline, points to the left side. Lungs differ with respect to lobation: two lobes are found on the left and three lobes on the right side. The stomach and spleen are positioned on the left, whereas the liver and appendix are found on the right. In addition, the small intestine and colon coil asymmetrically.
|
|
Fig. 2. Left-right organizers and the flow model of symmetry breakage. (A) Left-right organizers (LROs) come in different forms (Blum et al., 2007). In zebrafish, the LRO is known as Kupffer's vesicle and is a closed sphere. In Xenopus, the gastrocoel roof plate (GRP) acts as the LRO and is a flat triangular to diamond-shaped epithelium. In mouse, the LRO (the posterior notochord/‘node’) is an indentation at the distal tip of the egg cylinder. In all cases the LRO is positioned at the posterior pole of the notochord (gray). Axes are indicated: a, anterior; p, posterior; l, left; r, right. (B) Depiction of leftward flow at the ciliated epithelium of an LRO. Motile and polarized cilia (positioned at the posterior pole of cells) rotate in a clockwise fashion to produce a leftward fluid flow in the extracellular space. Flow is sensed by unpolarized cilia on cells bordering the LRO. In mouse and Xenopus these cilia have been described as being immotile (Boskovski et al., 2013; McGrath et al., 2003). These cells express both Nodal and the Nodal inhibitor Coco. As a result of flow, Coco becomes downregulated on the left side (Hojo et al., 2007; Nakamura et al., 2012; Schweickert et al., 2010), thereby derepressing and liberating Nodal protein. Also shown is the transfer of an unidentified asymmetric signal (likely to be Nodal protein; blue octagon labeled with question mark) to the left lateral plate mesoderm (LPM), where the Nodal cascade is induced. Nodal transfers across the somites and intermediate mesoderm (not shown) to the LPM, where it induces its own transcription and that of its feedback inhibitor Lefty as well as expression of Pitx2.
|
|
Fig. 3. Organ asymmetry evolved to store a regionalized and long gut tube. (A) The regionalized (as represented by the color gradient) gastrointestinal (GI) tract of a snail. Note that its length exceeds that of the main body axis. A compartmentalized GI tract that exceeds body length will inevitably be packaged asymmetrically. (B) We hypothesize that the urbilaterian GI tract was also regionalized and asymmetrically arranged. D, dorsal; V, ventral; other axes as Fig. 2.
|
|
Fig. 4. Cilia in the sea urchin gastrula embryo. Schematic of the dorsal half of a late gastrula sea urchin embryo. We speculate that archenteron (ac) cells are ciliated (A), and that cilia are polarized and produce a leftward fluid flow (B, green arrow). Nodal-expressing cells at the archenteron tip are in blue.
|
|
Fig. 5. Asymmetry in amphioxus. (A) Subadult animal (before differentiation of the gonads). Histological transverse (B) and longitudinal (C-E) sections of adult animals. The longitudinal sections were taken at the level of the dorsal muscle, dorsal to the neural tube (nt; C), at the level of the notochord (no; D) and at the level of the neural tube (E). Note the asymmetric body plan as reflected in the placement of the pharynx (ph), cecum (ce) and testes (te), and the alignment of muscles [myomeres (my)], nerve (n) and nerve fibers (nf). ar, fixation artifact; Rf, Reissner's fiber. (F) Reproduction of original drawings from Conklin's 1932 description of embryogenesis in amphioxus [reproduced with permission (Conklin, 1932)]. At 18 h post-fertilization (18 hpf, top), the somites are symmetrically aligned. However, by 24 hpf (bottom), somitogenesis has become out of register, as is obvious from the seventh somite onwards. The fourth (top) and seventh (bottom) somites are boxed in red. d, dorsal; l, left; r, right; v, ventral.
|
|
Fig. 6. Homology between amphioxus and Xenopus gastrocoel roof plates. Schematics of the gastrocoel roof plates (GRPs) of amphioxus (A,B) and Xenopus (C). Dorsal views of late gastrula (A) and 11.5 h neurula (B) embryos are shown (left) together with transverse sections (right) at the levels indicated. Nodal mRNA expression (blue) in amphioxus becomes asymmetric during early neurulation. Cells that are Nodal positive at late gastrula bud off from the archenteron roof to form the somites. At later stages, the epithelium in between the Nodal-positive cells likewise buds off to become the notochord (not indicated). Drawn according to Yu et al. (Yu et al., 2002). Cilia and flow at the notochordal part of the archenteron are a hypothetical prediction of the authors. (C) Schematic transverse section through a stage 17 Xenopus neurula embryo. Drawn according to Schweickert et al. (Schweickert et al., 2007). Note the striking homology between amphioxus and Xenopus GRPs: in both cases, lateral cells expressing Nodal are fated to become somites while central cells fold off to form (amphioxus) or integrate into (frog) the notochord. no, notochord; np, neural plate; som, somite.
|
|
Fig. 7. Divergent modes of symmetry breakage in vertebrates. (A) Ancestral flow-based mode of chordates. The early gastrula organizer (node), which expresses Nodal (blue), differentiates into the notochord and somites during early neurulation. The notochord does not express Nodal and thus splits the Nodal-positive domain down the middle. Nodal-positive cells later integrate into the somites. (B) Divergent mechanism in chick and pig. The organizer (node) rotates during early gastrulation, which renders the node left-asymmetric. The notochord emerges over the right shoulder of the node and does not split the Nodal domain. Nodal thus becomes displaced to the left without the need for flow.
|
