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In vertebrates, laterality - the asymmetric placement of the viscera including organs of the gastrointestinal system, heart and lungs - is under the genetic control of a conserved signaling pathway in the left lateral plate mesoderm (LPM). A key feature of this pathway, shared by embryos of all non-avian vertebrate classes analyzed to date (e.g. fish, amphibia and mammals) is the formation of a transitory midline epithelial structure. Remarkably, the motility of cilia projecting from this epithelium produce a leftward-directed movement of extracellular liquid. This leftward flow precedes any sign of asymmetry in gene expression. Numerous analyses have shown that this leftward flow is not only necessary, but indeed sufficient to direct laterality. Interestingly, however, cilia-independent mechanisms acting much earlier in development in the frog Xenopus have been reported during the earliest cleavage stages, a period before any major zygotic gene transcription. The relationship between these two distinct mechanisms is not understood. In this review we present the conserved and critical steps of Xenopus LR axis formation. Next, we address the basic question of how an early asymmetric activity might contribute to, feed into, or regulate the conserved cilia-dependent pathway. Finally, we discuss the possibility that Spemann's organizer is itself polarized in the left-right dimension. In attempting to reconcile the sufficiency of the cilia-dependent pathway with potential earlier-acting asymmetries, we offer a general practical experimental checklist for the Xenopus community working on the process of left-right determination. This approach indicates areas where work still needs to be done to clarify the relationship between early determinants and cilia-driven leftward flow.
Fig. 1.
LR development in Xenopus laevis. (A,A′) The superficial mesoderm (SM; green) constitutes the outer cell layer of Spemann's organizer and is located animally to the dorsal lip (dl). Mesodermal cells in the deepmarginal zone are colored red. (A) dorsal view of early gastrula, (A′) sagittal section. (B,B′) Following SM invagination, the ciliated gastrocoel roof plate (GRP) differentiates at the posterior archenteron (ac) in neurula embryos. Note GRP is not covered with endoderm (yellow) and flanked by lateral endodermal cells (LEC). Ciliated GRP cells cover dorsal aspects of the circumblastoporal collar (cbc) and blastoporus (bp), as well. Note also that lateral somitic GRP cells (blue) are unique for co–expressing the secreted growth factors Xnr1 and Coco and project cilia centrally. (B) st. 17 neurula midsagittal section, (B′) ventral view on GRP. GRP cilia. Immunohistochemistry using anti-acetylated tubulin antibody; ventral view. (D,E) The Nodal inhibitor Coco is the target of leftward flow. Schematic dorsal explants of early (D; pre-flow) and late (E; post-flow) neurulae in ventral view. (D) GRP (green) is flanked by a bilateral symmetric expression of Xnr1 (purple) and Coco (blue) in somitic GRP cells. Lateral plate mesoderm (LPM) is devoid of asymmetric gene activity. (E) Flow dependent left asymmetric downregulation of Coco mRNA releases Xnr1 from Coco repression. Transfer of left positional information by the relieved Xnr1 protein, induces Xnr1 transcription in the leftLPM. (F) Time course of events important in left–right specification. Stages indicated are according to Nieuwkoop and Faber (1967). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2.
Targeted tissues and LR processes of hypothetical early determinants. Xenopus 4-cell embryos could hypothetically harbor four possible asymmetries along the dorso-ventral axis; dorsal-right, dorsal-left, ventral-right and ventral-left (blue). Based on the restricted cell-lineage asymmetric early determinants could target different tissues, which are superimposed with blue color on neurula-stage embryos, respectively. GRP location inside the archenteron is shown as green triangles. The respective consequences on the LR pathway in the targeted tissue are indicated. For comparison symmetric dorsal and ventral factors that could act on leftâright development are shown as well. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 3.
Spemannâs organizer independent LR axis formation. Prediction of laterality in rescued UV irradiated embryos. 4-cell stage embryos with hypothetical predetermined LR axis are shown (red, right; uncolored, left). Endogenous ventral and dorsal blastomeres are indicated by sperm symbols (entry site) and circles (former organizer), respectively. Following UV irradiation and thus elimination of endogenous organizer, rescue could be targeted to four distinct positions (yellow star) relative to initial dorso-ventral (DV) and hypothetical pre-determined leftâright axes. Organizer rescues could be performed at initial dorsal or ventral (sperm entry) side or at a 90° angle to initial DV axis, thus at left or right blastomeres. Induced dorso-ventral axes are indicated (dâv). Cell fates of hypothetically predetermined left and right blastomeres are superimposed on neurula specimens (red, right; uncolored, left). If LR axis would be prefixed, UV rescued embryos should predictably display different laterality phenotypes depending on site of rescue. Asymmetric organ placements range from wild-type (situs solitus), mirror image (situs inversus) to randomization of single organs (heterotaxia). Note the differences in the frequency of wild-type situs solitus between prediction of an early prepatterned LR axis and the published experimental data by Vandenberg and Levin (2010) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).
