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First published online July 11, 2006
doi: 10.1242/10.1242/dev.02470
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
Pitx2ASE/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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