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Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis

Abstract

Pitx1 (refs 1,2,3) and Pitx2 (refs 4, 5) are highly homologous, bicoid-related transcription factors. Pitx2 was initially identified as the gene responsible for the human Rieger syndrome4, an autosomal dominant condition that causes developmental abnormalities. Pitx2 is asymmetrically expressed in the left lateral-plate mesoderm5,6,7,8,9,10,11, and mutant mice with laterality defects show altered patterns of Pitx2 expression that correlate with changes in the visceral symmetry (situs). Ectopic expression of Pitx2 in the right lateral-plate mesoderm alters looping of the heart and gut and reverses body rotation in chick and Xenopus embryos6,7,8,9,10,11. Here we describe the phenotype of Pitx2 gene-deleted mice, characterized by defective body-wall closure, right pulmonary isomerism, altered cardiac position, arrest in turning and, subsequently, a block in the determination and proliferation events of anterior pituitary gland and tooth organogenesis. Thus, Pitx2 is a transcription factor that encodes ‘leftness’ of the lung.

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Figure 1: Targeted deletion of the Pitx2 genomic locus.
Figure 2: Role of Pitx2 in arrest of axial turning, cardiac development and lung asymmetry.
Figure 3: Role of Pitx2 in pituitary development.
Figure 4: Role of Pitx2 in tooth development.

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Acknowledgements

We thank E. Olson, B. Hogan, G. Martin, P. Sharp and P. Overbeek for helpful discussions; M. Treier, A. Gleiberman, R. Burgess, A Ryan and other members of the laboratory for critical advice, data and discussion; E. Olson, B. Hogan, and P. Gruss for critical reagents; M. Ayers for animal handling; P. Myer for her expertise in preparation of illustrations; and M. Fisher for manuscript preparation. P.B. is on leave from the Advanced Biotechnology Center/IST Genoa, Italy, and is supported by the American Italian Cancer Foundation (Bristol-Myers Squibb Foundation). M.G.R. is an Investigator with the Howard Hughes Medical Institute. This work is supported by NIH grants to M.G.R. and J.C.I.B., and the G. Harold and Leila Y. Mathers Charitable Foundation to J.C.I.B.

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Correspondence to Juan Carlos Izpisúa-Belmonte or Michael G. Rosenfeld.

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Lin, C., Kioussi, C., O'Connell, S. et al. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401, 279–282 (1999). https://doi.org/10.1038/45803

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