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First published online July 11, 2006
doi: 10.1242/10.1242/dev.02470

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Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs

¹ Developmental Genetics Group, Graduate School for Frontier Biosciences, Osaka University, and CREST, Japan Science and Technology Corporation (JST), 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
² Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.

^* Authors for correspondence (e-mail: shiratori{at}fbs.osaka-u.ac.jp; hamada{at}fbs.osaka-u.ac.jp)

Accepted 1 June 2006

Pitx2 is expressed in developing visceral organs on the left side and is implicated in left-right (LR) asymmetric organogenesis. The asymmetric expression of Pitx2 is controlled by an intronic enhancer (ASE) that contains multiple Foxh1-binding sites and an Nkx2-binding site. These binding sites are essential and sufficient for asymmetric enhancer activity and are evolutionarily conserved among vertebrates. We now show that mice that lack the ASE of Pitx2 (Pitx2^ASE/ASE mice) fail to manifest left-sided Pitx2 expression and exhibit laterality defects in most visceral organs, although the position of the stomach and heart looping remain unaffected. Asymmetric Pitx2 expression in some domains, such as the common cardinal vein, was found to be induced by Nodal signaling but to be independent of the ASE of Pitx2. Expression of Pitx2 appears to be repressed in a large portion of the heart ventricle and atrioventricular canal of wild-type mice by a negative feedback mechanism at a time when the gene is still expressed in its other domains. Rescue of the early phase of asymmetric Pitx2 expression in the left lateral plate of Pitx2^ASE/ASE embryos was not sufficient to restore normal organogenesis, suggesting that continuous expression of Pitx2 in the lineage of the left lateral plate is required for situs-specific organogenesis.

Key words: Left-right asymmetry, Organogenesis, Pitx2, Mouse

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