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Conjoined twins occur at low frequency in all vertebrates including humans. Many twins fused at the chest or abdomen display a very peculiar laterality defect: while the lefttwin is normal with respect to asymmetric organ morphogenesis and placement (situs solitus), the organ situs is randomized in right twins. Although this phenomenon has fascinated already some of the founders of experimental embryology in the 19th and early 20th century, such as Dareste, Fol, Warynsky and Spemann, its embryological basis has remained enigmatic. Here we summarize historical experiments and interpretations as well as current models, argue that the frog Xenopus is the only vertebrate model organism to tackle the issue, and outline suitable experiments to address the question of twin laterality in the context of cilia-based symmetry breakage.
Figure 1. Examples of conjoined human and animal twins from the collection of Johann Friedrich Meckel the older. (AâC) Human dicephalic (A), thoracopagus (B) and cephalothoracopagus (C) specimens. (D) Dicephalic cattle. (E) Thoracopagus sheep. (F) Meckel's four-legged rooster, that reportedly roamed Meckel's chicken run for 3 years. Reproduced from Schultka (2012) with permission
Figure 2. Thoracopagus Xenopus twin tadpoles. (A) Thoracopagus conjoined twins in Xenopus laevis can be generated by injection of Wnt-pathway components into the ventral marginal zone of cleavage stage embryos. Depending on whether left or rightventral blastomeres are injected, the induced twins are placed on the left or right side of the endogenous twin. (B–C) Genesis of conjoined twins. Histological vibratome sections of st. 17 (B’–B’’’), st. 20 (C’–C’’’) and st. 32 (D’–D’’’) conjoined twins (B–D) demonstrate the thoracopagus character of twins. At stage 17 and 22, two separate notochords are present throughout (filled arrowheads), which fuse at the posterior end during tadpole stages (D’’’, st. 32). Normal sized somites are present lateral to both notochords and a large fused somite in between (open arrowheads in B’–B’’’, C’–C’’’, D’, D’’). Blue shading, notochord; pink shading, somites
Figure 3. âIon-fluxâ model of symmetry breakage in wt embryos and conjoined twins (adapted from various publications from M. Levin; cf., references). (A, B) According to this model, wildtype embryos establish asymmetrical nodal1 expression in the LPM at st. 22 via an asymmetric distribution of serotonin during early cleavage stages. (CâE) In artificially induced conjoined twins (C), late organizers can only instruct a wildtype arrangement of inner organs (st.45) if they give rise to the left twin (iL), that obtained ion-flux prepatterning during cleavage stages (D). Right-sided late organizers (iR) miss prepatterning information and therefore orient the heart randomly (E). Ion-flux prepatterning (yellow), nodal1 LPM expression (purple), induced twin (pink), endogenous twin (black). ABP, apico-basal polarity genes and proteins; PCP, planar cell polarity genes and proteins. B redrawn from Blum et al. (2014b)
Figure 4. Cilia- and leftward flow-driven mode of symmetry breakage in Xenopus. (A–C) The ciliated GRP develops from the superficial mesoderm (SM), which expresses the motile cilia transcription factor foxj1, and which invaginates during gastrulation. (D–G) Polarized cilia at the center of the GRP produce a leftward flow of extracellular fluids (D), which represses the Nodal inhibitor dand5 in the lateral GRP cells (E) to de-repress the co-expressed Nodal (F) and induce the asymmetric Nodal signaling cascade in the leftLPM (G)
