Laterality defects are influenced by timing of treatments and animal model

Abstract

The timing of when the embryonic left-right (LR) axis is first established and the mechanisms driving this process are subjects of strong debate. While groups have focused on the role of cilia in establishing the LR axis during gastrula and neurula stages, many animals appear to orient the LR axis prior to the appearance of, or without the benefit of, motile cilia. Because of the large amount of data available in the published literature and the similarities in the type of data collected across labs, I have examined relationships between the studies that do and do not implicate cilia, the choice of animal model, the kinds of LR patterning defects observed, and the penetrance of LR phenotypes. I found that treatments affecting cilia structure and motility had a higher penetrance for both altered gene expression and improper organ placement compared to treatments that affect processes in early cleavage stage embryos. I also found differences in penetrance that could be attributed to the animal models used; the mouse is highly prone to LR randomization. Additionally, the data were examined to address whether gene expression can be used to predict randomized organ placement. Using regression analysis, gene expression was found to be predictive of organ placement in frogs, but much less so in the other animals examined. Together, these results challenge previous ideas about the conservation of LR mechanisms, with the mouse model being significantly different from fish, frogs and chick in almost every aspect examined. Additionally, this analysis indicates that there may be missing pieces in the molecular pathways that dictate how genetic information becomes organ positional information in vertebrates; these gaps will be important for future studies to identify, as LR asymmetry is not only a fundamentally fascinating aspect of development but also of considerable biomedical importance.

Conserved roles for cytoskeletal components in determining laterality

“…3A,B) while Xnr1, Lefty and Pitx2 laterality can be closely predictive of organ situ in others (Figure 5), suggests that Nodal signaling is not necessarily a definitive determinant of final morphological outcome. This has been noted in other pathways in multiple model systems (49) and the absent Nodal expression in embryos that grow up to be normal (7% of control embryos show no expression of Xnr1, e.g. Figure 2C) that we have observed previously (see Figure 7 in (54)) underscores that Nodal is not a definitive marker of laterality.…”

Serotonin has early, cilia-independent roles inXenopusleft-right patterning

“…1A), not pitx2 expression as in other studies (Beyer et al, 2012), because incidence of incorrect asymmetric gene expression strongly overestimates the effects of treatments on randomizing organ situs, making cilia-targeting treatments appear more penetrant than they are (supplementary material Fig. S1) (Vandenberg, 2012). Whereas the LATE model predicts that there should be no effect from ectopic serotonin on either side, the EARLY model predicts that excess serotonin signaling, especially on the left side, will randomize the LR axis by ectopic activation of intracellular receptors (Carneiro et al, 2011).…”

From cytoskeletal dynamics to organ asymmetry: a nonlinear, regulative pathway underlies left–right patterning

“…The details remain to be characterized. It should be noted however that another potential layer of complexity in these stochastic data could be due to the possibility that different embryos from the same batch might be relying on somewhat different mechanisms for LR asymmetry (discussed in detail in [214]). …”