<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>All internal organs are asymmetric along the left–right axis. Here we report a genetic
screen to discover mutations which perturb organ laterality. Our particular focus is upon
whether, and how, organs are linked to each other as they achieve their laterally
asymmetric positions. We generated mutations by ENU mutagenesis and examined F3
progeny using a cocktail of probes that reveal early primordia of heart, gut, liver and
pancreas. From the 750 genomes examined, we isolated seven recessive mutations which
affect the earliest left–right positioning of one or all of the organs. None of these mutations
caused discernable defects elsewhere in the embryo at the stages examined. This is in
contrast to those mutations we reported previously (Chen <italic>et al.</italic>, 1997) which, along with
left–right abnormalities, cause marked perturbation in gastrulation, body form or midline
structures. We find that the mutations can be classified on the basis of whether they
perturb relationships among organ laterality. In Class 1 mutations, none of the organs
manifest any left–right asymmetry. The heart does not jog to the left and normally leftpredominant
<italic>BMP4</italic> in the early heart tube remains symmetric. The gut tends to remain
midline. There frequently is a remarkable bilateral duplication of liver and pancreas.
Embryos with Class 2 mutations have organotypic asymmetry but, in any given embryo,
organ positions can be normal, reversed or randomized. Class 3 reveals a hitherto
unsuspected gene that selectively affects laterality of heart. We find that visceral organ
positions are predicted by the direction of the preceding cardiac jog. We interpret this as
suggesting that normally there is linkage between cardiac and visceral organ laterality.
Class 1 mutations, we suggest, effectively remove the global laterality signals, with the
consequence that organ positions are effectively symmetrical. Embryos with Class 2
mutations do manifest linkage among organs, but it may be reversed, suggesting that the
global signals may be present but incorrectly orientated in some of the embryos. That
laterality decisions of organs may be independently perturbed, as in the Class 3 mutation,
indicates that there are distinctive pathways for reception and organotypic interpretation
of the global signals.</p>
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Comp Funct Genomics. 2001 Apr; 2(2):60-68