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.
Highlights
The 22q11.2 deletion syndrome (22q11.2DS), known as velo-cardio-facial syndrome (MIM# 192430) or DiGeorge syndrome (MIM# 188400) is a congenital malformation disorder that is caused by a hemizygous 1.5–3 million base pair (Mb) deletion of chromosome 22q11.2
To identify downstream genes affected by these changes, gene expression profiling was performed on the distal pharyngeal apparatus containing the anterior heart field (AHF) micro-dissected from β-cat LOF and β-cat GOF embryos at E9.5 (Fig 1F– 1H)
We examined cardiac phenotypes upon inactivation of Tbx1 in the Mef2c-AHF-Cre lineage to determine whether Tbx1 had a specific role in the AHF
Summary
The 22q11.2 deletion syndrome (22q11.2DS), known as velo-cardio-facial syndrome (MIM# 192430) or DiGeorge syndrome (MIM# 188400) is a congenital malformation disorder that is caused by a hemizygous 1.5–3 million base pair (Mb) deletion of chromosome 22q11.2. It occurs with a frequency of 1:1,000 fetuses [1] and 1:4,000 live births [2]. TBX1 has been considered the strongest candidate gene for CHD, based upon studies of mouse models [5,6,7] and discovery of mutations in some non-deleted patients [8, 9]. We are taking mouse genetic approaches to identify genes and networks that may act as modifiers
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