title: Reduced dosage of β-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome.
abstract: The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/β-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in β-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of β-catenin were inactivated in the Mef2c-AHF-Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, β-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Silvia E
authors.identifier: 0000-0002-1557-7510
authors.initials: SE
authors.lastname: Racedo
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Erica
authors.identifier: 0000-0001-6812-9837
authors.initials: E
authors.lastname: Hasten
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Gnanapackiam Sheela
authors.initials: GS
authors.lastname: Devakanmalai
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Tingwei
authors.identifier: 0000-0002-9320-543X
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Ertugrul M
authors.initials: EM
authors.lastname: Ozbudak
authors.affiliation: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Chen-Leng
authors.initials: CL
authors.lastname: Cai
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.|Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States of America.|Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Deyou
authors.identifier: 0000-0003-4354-5337
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States of America.
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018376:Cardiovascular Abnormalities / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000235:genetics; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014338:Truncus Arteriosus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051176:beta Catenin