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Fig. 1. Heterotaxia induced by H+-V-ATPase inhibitors.
Xenopus embryos were soaked in inhibitors of various ion
transporters. The percent of embryos considered heterotaxic (defined as a
reversal of at least one from the heart, gut or gall bladder) is calculated
relative to the total number of embryos, most of which showed normal
laterality. Inhibitors of H+-V-ATPase (A) caused significant
levels of heterotaxia, while inhibitors of other proton pumps
(B,C) or of other transporters (D-J) had no effect on
laterality. Inhibitor names and sample sizes are listed above the bars;
targets and doses of drugs in B-J are listed in
Table 1. Complete randomization
of three organs would lead to a maximum heterotaxia rate of 87.5%, as, by
chance, organ situs will appear to be wild type in 12.5% of embryos.
(K) A wild-type embryo, ventral view, showing the normal arrangement of
the gut (yellow arrowhead), heart apex (pink arrowhead) and gall bladder
(green arrowhead). (K') Higher magnification of normal heart. (L) A
heterotaxic embryo (ventral view) showing reversal of all three organs, i.e.
situs inversus. (L') Close-up of reversed heart. Image contrast has been
enhanced for clarity, and the loop of the heart has been outlined with black
dots in K and L. Drugs used for this screen were titered to determine a dose
that will cause heterotaxia without causing other morphological defects;
(M) an example titration curve for concanamycin. The asterisk in M
corresponds to the datum used in A (115 nM). There is a degree of variability
among sensitivity of embryos obtained from different females; toxicity
(defined as the percent of embryos dying post-gastrulation and/or developing
with significant morphological defects) increases at larger concentrations,
and there is only a narrow range of useful doses. The dose that is toxic to
50% of embryos (TD50; corrected for control background lethality of
9%) was 234 nM.
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