Pitx2 determines left–right asymmetry of internal organs in vertebrates

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Abstract

The handedness of visceral organs is conserved among vertebrates and is regulated by asymmetric signals relayed by molecules such as Shh, Nodal and activin. The gene Pitx2 is expressed in the left lateral plate mesoderm and, subsequently, in the left heart and gut of mouse, chick and Xenopus embryos. Misexpression of Shh and Nodal induces Pitx2 expression, whereas inhibition of activin signalling blocks it. Misexpression of Pitx2 alters the relative position of organs and the direction of body rotation in chick and Xenopus embryos. Changes in Pitx2 expression are evident in mouse mutants with laterality defects. Thus, Pitx2 seems to serve as a critical downstream transcription target that mediates left–right asymmetry in vertebrates.

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Figure 1: Pitx2 is expressed asymmetrically in the lateral plate mesoderm, heart and gut.
Figure 4: Expression of Pitx2 is altered in iv and inv mice.
Figure 2: Pitx2 is downstream of Sonic hedgehog and Nodal.
Figure 3: Ectopic expression of Pitx2 affects left–right asymmetry of the heart and the gut.
Figure 5: ActRII-ECD binds activin.
Figure 6: A dominant negative activin receptor alters expression of nodal and Pitx2 and causes reversal of heart looping.

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Acknowledgements

We thank E. Leonardo for her technical skills and dedication; F. H. Gage for access to the confocal laser scanning microscope; D. Peterson for assistance with confocal imaging; C. Tabin for sharing unpublished results; C. V. E. Wright, C. Tabin and L. Erkman and B. Eshelman for reagents and for discussion; J.Magallon and B. Eshelman for technical assistance; and L. Hooks and P. Myer for preparaing the manuscript. S.Y.T. and K.T. were supported by the J.S.P.S. M.G.R. and R.M.E. are investigators of the Howard Hughes Medical Institute; J.C.I.B. is a Pew Scholar. J.G is a HHMI predoctoral fellow. This work was supported by NIH grants to M.G.R., R.M.E. and J.C.I.B., by a G. Harold and Leila Y. Mathers Charitable Foundation grant to R.M.E., S.C., and J.C.I.B.

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Correspondence to Juan Carlos Izpisúa Belmonte.

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Ryan, A., Blumberg, B., Rodriguez-Esteban, C. et al. Pitx2 determines left–right asymmetry of internal organs in vertebrates. Nature 394, 545–551 (1998) doi:10.1038/29004

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