Targeted Disruption of CalciumNFAT Signaling Reveals a Left-Right Determination Disorder in the Pharyngeal Arch Artery

Abstract EN

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.