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. 1. Introduction Recently there have been reports that the immune response controls vertebrate morphogenesis. Mukaigasa et al. [1] indicated a role for the immune response in metamorphosis, based on the finding that syngeneic grafts of tadpole tail skin into adult Xenopus animals are rejected by T cells. I reported that lens regeneration in newt eyes was induced by antigen-presenting cells that had engulfed the remains of the destroyed lens [2]. Amphibians are the most commonly used models in this field, and there is little experimental data for the role of the immune response in morphogenesis of mammals. 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]. The early embryonic mammalian system consists of five paired arch arteries, numbered I to VI from cranial to caudal. The fifth artery is considered to be rudimentary or absent. 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
References
[1]
K. Mukaigasa, A. Hanasaki, M. Maéno et al., “The keratin-related Ouroboros proteins function as immune antigens mediating tail regression in Xenopus metamorphosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 43, pp. 18309–18314, 2009.
[2]
T. Kanao and Y. Miyachi, “Lymphangiogenesis promotes lens destruction and subsequent lens regeneration in the newt eyeball, and both processes can be accelerated by transplantation of dendritic cells,” Developmental Biology, vol. 290, no. 1, pp. 118–124, 2006.
[3]
T. Hiruma and Y. Nakajima, “Development of pharyngeal arch arteries in early mouse embryo,” Journal of Anatomy, vol. 201, no. 1, pp. 15–29, 2002.
[4]
G. R. Crabtree, “Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT,” Cell, vol. 96, no. 5, pp. 611–614, 1999.
[5]
C. Cursiefen, L. Chen, L. P. Borges et al., “VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment,” Journal of Clinical Investigation, vol. 113, no. 7, pp. 1040–1050, 2004.
[6]
J. C. Boisset, W. Van Cappellen, C. Andrieu-Soler, N. Galjart, E. Dzierzak, and C. Robin, “In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium,” Nature, vol. 464, no. 7285, pp. 116–120, 2010.
[7]
J. Capdevila, K. J. Vogan, C. J. Tabin, and J. C. Izpisúa Belmonte, “Mechanisms of left-right determination in vertebrates,” Cell, vol. 101, no. 1, pp. 9–21, 2000.
[8]
X. Yuan, P. Simpson, C. McKeown et al., “Structure, dynamics and interactions of p47, a major adaptor of the AAA ATPase, p97,” The EMBO Journal, vol. 23, no. 7, pp. 1463–1473, 2004.
[9]
H. Shiratori and H. Hamada, “The left-right axis in the mouse: from origin to morphology,” Development, vol. 133, no. 11, pp. 2095–2104, 2006.
[10]
J. McGrath, S. Somlo, S. Makova, X. Tian, and M. Brueckner, “Two populations of node monocilia initiate left-right asymmetry in the mouse,” Cell, vol. 114, no. 1, pp. 61–73, 2003.
[11]
Y. Tanaka, Y. Okada, and N. Hirokawa, “FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination,” Nature, vol. 435, no. 7039, pp. 172–177, 2005.
[12]
M. Hatayama, K. Mikoshiba, and J. Aruga, “IP3 signaling is required for cilia formation and left-right body axis determination in Xenopus embryos,” Biochemical and Biophysical Research Communications, vol. 410, no. 3, pp. 520–524, 2011.
[13]
M. Levin, T. Thorlin, K. R. Robinson, T. Nogi, and M. Mercola, “Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left-right patterning,” Cell, vol. 111, no. 1, pp. 77–89, 2002.
[14]
S. B. Helliwell, P. Wagner, J. Kunz, M. Deuter-Reinhard, R. Henriquez, and M. N. Hall, “TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast,” Molecular Biology of the Cell, vol. 5, no. 1, pp. 105–118, 1994.
