Human Molecular Genetics Advance Access published online on September 25, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl399
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1 Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
* To whom correspondence should be addressed. The 22q11 deletion syndrome (22q11DS) is characterized by abnormal development of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1 as a key gene in the etiology of the syndrome, in part via interaction with the fibroblast growth factor (Fgf) genes. Three murine Fgfs, Fgf3, Fgf8 and Fgf10 are coexpressed in different combinations with Tbx1. They are all strongly downregulated in Tbx1-/- embryos, implicating epistatic interactions. Supporting this, Tbx1 and Fgf8 have been shown to genetically interact in development of the fourth pharyngeal arch artery and Fgf10 was identified to be a direct downstream target of Tbx1. To dissect the epistatic relationships of these genes during embryonic development and the molecular pathogenesis of the Tbx1 mutant phenotype, we generated Fgf10+/-; Tbx1+/- and Fgf3-/-; Tbx1+/- mice. Despite strong hypotheses that Fgf10 is the key gene downstream of Tbx1 in the development of the anterior heart field, we do not find evidence for genetic interaction between Tbx1 and Fgf10. Also, the Fgf3-/-; Tbx1+/- mutant mice do not show an additive phenotype. Furthermore, more severe defects do not occur in Fgf8+/-; Tbx1+/- mutants by crossing in the Fgf3 null allele. There is a possible additive effect only in pharyngeal arch artery remodeling in the Fgf10+/-; Tbx1+/-; Fgf8+/- embryos. Our findings underscore the importance of potential functional redundancy with additional Fgfs in the development of the pharyngeal apparatus and cardiovascular system via Tbx1. This redundancy should be considered when looking at individual FGF genes as modifiers of 22q11DS.
Received August 2, 2006
Revised September 18, 2006
Accepted September 18, 2006
Article
Dissection of Tbx1 and Fgf interactions in mouse models of 22q11DS suggests functional redundancy
Vimla S. Aggarwal 1, Jun Liao 1, Alexei Bondarev 1, Thomas Schimmang 2, Mark Lewandoski 3, Joseph Locker 4, Alan Shanske 5, Marina Campione 6, and Bernice E. Morrow 1 *
2 Institute for Biology and Molecular Genetics, Superior Research Council and University of Valladolid, E-47003 Valladolid, Spain
3 Genetics of Vertebrate Development Section, National Cancer Institute, Frederick Cancer Research & Development Center, Box B, Building 539, Frederick, Maryland 21702, USA
4 Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
5 Center for Craniofacial Disorders, CHAM, 1345 Bainbridge Avenue, Bronx, NY 10467, USA
6 CNR-Institute of Neurosciences, Department of Biomedical Sciences, University of Padova, Padova, Italy
Bernice E. Morrow, E-mail: morrow{at}aecom.yu.edu
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