TY  - THES
T1  - Towards a unifying model of symmetry breakage in Xenopus laevis : serotonin signaling and the cilia-driven leftward flow
A1  - Thumberger,Thomas
Y1  - 2012/10/08
N2  - Orientation of the three vertebrate body axes anterior-posterior (AP), dorso-ventral (DV) and left-right (LR) is specified during early embryogenesis. Whereas the formation of the AP and DV axes is well understood, it is not finally resolved how and when the left and right sides get molecularly distinct. All deuterostomes analyzed so far, however, display an asymmetric left-sided expression of the TGF-β factor Nodal during embryonic development which precedes asymmetric organogenesis. In zebrafish, medaka, mouse and rabbit embryos a cilia-driven extracellular leftward fluid flow was shown to be causal for the left asymmetric induction of the Nodal gene cascade during early neurulation. In X. laevis, leftward flow was also shown to be driven by a mono-ciliated epithelium in the posterior part of the archenteron roof (gastrocoel roof plate, GRP). Mechanical blockage of this current resulted in laterality defects. Despite the apparent evolutionary conservation of flow, an earlier mechanism to specify the LR axis during early cleavage stages has been reported in X. laevis. Based on mostly inhibitor experiments, the so-called 'ion-flux' hypothesis was put forward which proposes an electrogenic transport and asymmetric accumulation of determinants as early as at the 32-64 cell stage. The monoamine serotonin is the core-effector of this hypothesis and was reported to asymmetrically accumulate at the ventral right blastomeres of early cleavage stage embryos. 
The aim of this study was to investigate putative interactions of the two apparently opposing mechanisms for breaking the initial LR symmetry of the Xenopus zygote. Reinvestigation of serotonin localization could not confirm the initial report. Further, serotonin signaling was shown to be necessary for LR axis formation on the dorsal but not ventral side, more specifically as a competence factor for the canonical Wnt-pathway. Detailed analyses of specimens impaired for serotonin signaling revealed requirement of serotonin signaling for specification of the superficial mesoderm (SM) which gives rise to the GRP and, consequently, to leftward flow. Leftward flow thus indirectly depends on dorsal serotonin signaling.
In a further part of the present thesis, a re-examination of laterality in Siamese twins was performed. It has been known since the earliest experimental investigations of laterality that in induced and naturally occurring Siamese twins the left twin consistently displays wildtype orientation of the visceral organs whereas the orientation in the right twin is randomized. In experimentally induced conjoined twins, this observation holds true regardless of which twin is the induced. A model of symmetry breakage, in order to be plausible, thus should also be able to account for this phenomenon. When experimentally induced twins were analyzed for leftward flow, in the majority of cases a continuous leftward flow was observed, i.e. both twins shared one GRP. Thus, laterality cue(s) get translocated towards the far left side, i.e. only the left embryo receives the wildtype asymmetric information, regardless if it is the induced or endogenous twin. In rare case X. laevis conjoined axes developed far apart from one another such that two separate GRPs and individual leftward flows were observed, a condition that enabled both axes to exhibit a left-sided Nodal cascade. These experiments strongly suggest that Spemann's organizer itself is necessary and sufficient to establish all three body axes.
In conclusion, the present analysis of laterality determination in the frog Xenopus supports evolutionary conservation of leftward flow as symmetry breaking event, as previously reported for mouse, rabbit and bony fish.
KW  - Lateralität
KW  - Entwicklungsbiologie
KW  - Serotonin
KW  - Krallenfrosch
KW  - Siamesische Zwillinge
CY  - Hohenheim
PB  - Kommunikations-, Informations- und Medienzentrum der Universität Hohenheim
AD  - Garbenstr. 15, 70593 Stuttgart
UR  - http://opus.uni-hohenheim.de/volltexte/2012/765
ER  -