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Development
2006 Apr 01;1337:1399-410. doi: 10.1242/dev.02292.
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Left-right lineage analysis of the embryonic Xenopus heart reveals a novel framework linking congenital cardiac defects and laterality disease.
Ramsdell AF
,
Bernanke JM
,
Trusk TC
.
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The significant morbidity and mortality associated with laterality disease almost always are attributed to complex congenital heart defects (CHDs), reflecting the extreme susceptibility of the developing heart to disturbances in the left-right (LR) body plan. To determine how LR positional information becomes ;translated' into anatomical asymmetry, left versus right side cardiomyocyte cell lineages were traced in normal and laterality defective embryos of the frog, Xenopus laevis. In normal embryos, myocytes in some regions of the heart were derived consistently from a unilateral lineage, whereas other regions were derived consistently from both left and right side lineages. However, in heterotaxic embryos experimentally induced by ectopic activation or attenuation of ALK4 signaling, hearts contained variable LR cell composition, not only compared with controls but also compared with hearts from other heterotaxic embryos. In most cases, LR cell lineage defects were associated with abnormal cardiac morphology and were preceded by abnormal Pitx2c expression in the lateral plate mesoderm. In situs inversus embryos there was a mirror image reversal in Pitx2c expression and LR lineage composition. Surprisingly, most of the embryos that failed to develop heterotaxy or situs inversus in response to misregulated ALK4 signaling nevertheless had altered Pitx2c expression, abnormal cardiomyocyte LR lineage composition and abnormal heart structure, demonstrating that cardiac laterality defects can occur even in instances of otherwise normal body situs. These results indicate that: (1) different regions of the heart contain distinct LR myocyte compositions; (2) LR cardiomyocyte lineages and Pitx2c expression are altered in laterality defective embryos; and (3) abnormal LR cardiac lineage composition frequently is associated with cardiac malformations. We propose that proper LR cell composition is necessary for normal morphogenesis, and that misallocated LR cell lineages may be causatively linked with CHDs that are present in heterotaxic individuals, as well as some 'isolated' CHDs that are found in individuals lacking overt features of laterality disease.
Fig. 1. Left-right lineage labeled embryo. Left and right cell lineages
were microinjected with Oregon Green-conjugated dextran (green) and
Alexa 647-conjugated dextran (red), respectively. Embryos were fixed
and confocal images of whole mounts were collected after labeled
embryos reached stages 45-46 (~5 days). A dorsal view of a labeled
embryo is shown.
Fig. 4. Left-right lineage composition in d-looped
hearts of heterotaxic embryos. Three different
hearts (A-C, D-G, H-K) show the right cardinal vein
(RCV), left cardinal vein (LCV), right aortic arch (RAA),
left aortic arch (LAA), atrioventricular canal (AVC),
ventricle (VEN) and outflow tract (OFT). All of the
hearts in this category contained an unseptated
common atrium (CA). Scale bar: 100 m.
Fig. 6. Left-right lineage composition in hearts of
experimental situs solitus embryos with right-side
CA-ALK4 expression. Three different hearts
(A-C, D-F, G-I) are shown. The right cardinal vein
(RCV), left cardinal vein (LCV), right aortic arch (RAA),
left aortic arch (LAA), atrioventricular canal (AVC),
ventricle (VEN), and outflow tract (OFT) are indicated.
The heart in A-C contains a normally developed left
atrium (LA) and right atrium (RA) separated by an
interatrial septum (IAS). The heart in D-F contains a
common atrium (CA) and the heart in G-I has inverted
atria, as indicated by the position of the morphological
left atrium (MLA) and morphological right atrium
(MRA), which are separated by an IAS. Scale bar:
100 m.
Fig. 7. Left-right lineage composition in hearts of
experimental situs solitus embryos with left-side
CA-ALK4 expression. Three different hearts
(A-C, D-G, H-J) are shown. The right cardinal vein
(RCV), left cardinal vein (LCV), right aortic arch (RAA),
left aortic arch (LAA), atrioventricular canal (AVC),
ventricle (VEN), outflow tract (OFT) and aortic sac (AS)
are indicated. The hearts in A-C and H-J each contain
an unseptated common atrium (CA). Scale bar:
100 m.
Fig. 8. Pitx2c expression in normal and laterality defective
embryos. Control and CA-ALK4-injected embryos were processed for
whole-mount in situ hybridization to detect Pitx2c expression
(arrowheads). (A) Control embryo, left-side view. (B) Right-side injected
embryo, left and right-side views. (C) Right-side injected embryo, rightside
view. (D) Left-side injected embryo, left-side view.
Fig. 9. Left-right lineage composition in hearts of
embryos situs following left-side DN-ALK4
expression. Three different hearts (A-C, D-F, G-I) are
shown. The right cardinal vein (RCV), left cardinal vein
(LCV), right aortic arch (RAA), left aortic arch (LAA),
atrioventricular canal (AVC), ventricle (VEN), outflow
tract (OFT) and aortic sac (AS) are indicated. Scale bar:
100 m.
Fig. 10. LR lineage composition of the normal heart. A threedimensional
schematic heart was created based on reconstructed serial
sections of several hearts in this study. The exterior was pseudo-painted
green and red to indicate left and right-side cell lineages, respectively.
The right cardinal vein (RCV), left cardinal vein (LCV), right aortic arch
(RAA), left aortic arch (LAA), left atrium (LA), right atrium (RA),
atrioventricular canal (AVC), ventricle (VEN), outflow tract (OFT) and
aortic sac (AS) are indicated in dorsal (A) and ventral (B) views.