Abstract
An immunosuppressant was injected into pregnant mice in order to investigate whether the immune response is involved in differentiation during embryonic development. Injection of 3 mg/kg of FK506, an inhibitor of calcineurin, early in the organogenesis period increased the penetrance of right aortic arch formation by 32% compared with saline injection. Immunosuppressants such as FTY720 and rapamycin did not affect left/right (L/R) determination. FK506 is known to work by restricting NFAT (nuclear factor activated T-cell) dephosphorylation. An L/R determination disorder in cardiac outflows appeared when an NFATc4 siRNA was directly injected into the amniotic fluid. As for the mechanism, Pitx2, which is normally expressed on the left-hand side, was found to be expressed also on the right-hand side. Furthermore, it turned out that administration of FK506 also prevented the dephosphorylation of NSFL1 cofactor p47. When an siRNA targeting p47 was introduced into the amniotic fluid of FK506-treated fetuses, both of the dorsal arteries—which should normally become one—remained. These findings indicate that the mother's immune system contributes not only to self defense, but also to remodeling processes in fetal morphogenesis.
Highlights
There have been reports that the immune response controls vertebrate morphogenesis
Injection of 3.0 mg/kg of FK506 into the mother mouse on days 6.5, 7.5, and 8.5 of pregnancy induced an L/R determination disorder, in which the cardiac outflow tract ascended toward the right side, formed an arch, and descended through the right side of the chest (Figures 1(b) and 1(d))
This study has clearly revealed that Pitx2, which is normally expressed at the left-hand side of embryos, is expressed at the right-hand side and promotes the formation of a right aortic arch when calcineurin is inhibited using FK506
Summary
There have been reports that the immune response controls vertebrate morphogenesis. The morphogenetic processes underlying pharyngeal arch artery (PAA) remodeling from the symmetrical configuration toward the unilateral left-sided aortic arch have not been fully unraveled [3]. At day 11.5 of pregnancy, the PAA system consists of a left and right third (III), fourth (IV), and sixth (VI) arch artery, connecting two continuous dorsal aortas with the ventrally located aortic sac. Around day 12 of pregnancy, the arterial system develops toward the mature left-sided configuration, due to regression of the right-sided sixth arch artery, the right dorsal aorta (α-segment), and both the left and right carotid ducts. I speculated that the immune response in mothers might act in the remodeling process of fetuses, as shown for amphibian development. To evaluate the possible causes of abnormalities in the cardiac outflow tract, fetuses taken from mothers injected with immunosuppressants were examined
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