XB-ART-56029Curr Opin Genet Dev June 1, 2019; 56 8-14.
Animal asymmetries are widespread, from lobster claws to human handedness. Controlled by the left-sided Nodal signaling cascade, asymmetric morphogenesis and placement of vertebrate organs (heart, gut, etc.) are executed during embryogenesis. Fish, amphibians and mammals use a ciliated epithelium to break bilateral symmetry and induce the Nodal cascade. Cilia tilt and polarize to the posterior cell pole, such that clockwise rotation causes a leftward flow at the cell surface. Recent progress in Xenopus showed that mechanical strain drives cilia lengthening and polarization. Studying mutant alleles causing human organ situs defects and following novel EvoDevo approaches, new genes were discovered and functionally characterized in the frog, facilitated by a unique set of experimental tools.
PubMed ID: 31185381
Article link: Curr Opin Genet Dev
Genes referenced: cfap53 ctnnb1 dand5 fgfr1 fgfr4 foxj1 foxj1.2 lefty myf5 myo1d myod1 nodal nodal1 nodal3.1 nodal3.4 pitx2 pkd2 rapgef5 sia2 wdr5
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|Figure 1. Outline of the basic sequence of symmetry breaking events in the frog Xenopus. (1) Foxj1 expression (green) in the early gastrula embryo marks the LRO precursor (superficial mesoderm), from which (2) the LRO derives when the SM involutes to line the roof of the primitive gut. (3) Central LRO cells harbor motile cilia which polarize to the posterior cell poles and rotate in a clockwise manner to generate a leftward flow of extracellular fluids. Lateral LRO cells possess immotile cilia and co-express nodal1 (blue) and the Nodal inhibitor dand5 (orange). Flow sensing at the left LRO margin results in dand5 down-regulation, which allows Nodal to signal and (4) transfer to the LPM. In the left LPM, (5) Nodal signaling induces the three target genes of the nodal cascade, nodal1 itself, the feedback inhibitor lefty1 and the homeobox transcription factor pitx2. Spreading of left-asymmetric signaling is prevented by lefty1 expression at the midline (notochord and floor plate). (6) The Nodal cascade in due course drives asymmetric organ morphogenesis. Timeline on the left indicates developmental stages. An animated version of this scheme can be found on the author’s home page (https://zoologie.uni-hohenheim.de/en/agembryology_eng).|
|Figure 2. Novel insights into specification, morphogenesis and function of the frog LRO. Induction of foxj1 in central LRO precursor cells requires canonical Wnt signaling as well as signaling through Fgfr1. The latter is activated by the unconventional FGF ligand Nodal3, synergizing with Polycystin-2, whereas the former requires rapgef5, which presumably regulates nuclear import of ß-catenin (Ctnnb1). Lateral flow-sensing LRO cells depend on FGF signaling through receptor 4, which activates myf5 and myod1 in these cells that are fated to integrate into the somites. Accessibility of the foxj1 promoter is regulated by methylation of histone H3 (H3K4me3); for assembly of the methyltransferase enzyme complex, Wdr5 constitutes a central scaffolding component. Mechanical strain (red arrows) exerted on the involuting LRO precursor causes PCP-dependent posterior polarization of LRO cilia, which become motile in a strain-dependent and foxj1-dependent manner. The foxj1 gradient of gene expression (cf. Figure 1) is reflected by a medial-lateral gradient of cilia lengths and polarization. PCP is acted upon as well by the unconventional myosin Myo1d. Novel ciliary factors acting on cilia include Wdr5 (at the ciliary base) and Ccdc11 as well as Enkur (in the ciliary axoneme). These factors await detailed functional characterization.|
|Figure 3. Organ situs determination in conjoined twins. Experimentally created conjoined Xenopus embryos harbor a fused LRO in which the left margin of the right twin’s LRO is fused to the right margin of the left one. Cilia-generated flow across the fused LRO represses dand5 and induces asymmetric LRO Nodal signaling only in the left twin, while flow is insufficient to de-repress nodal1 in the fused central domain. As a result, the right twin lacks a biased asymmetric LRO signal and organ asymmetry develops in a random fashion.|