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BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, characterized by cardiovascular defects such as interrupted aortic arch, outflow tract defects, thymus and parathyroid hypo- or aplasia, and cleft palate. Heterozygosity of Tbx1, the mouse homolog of the candidate TBX1 gene, results in mild defects dependent on genetic background, whereas complete inactivation results in severe malformations in multiple tissues. RESULTS: The loss of function of two Sprouty genes, which encode feedback antagonists of receptor tyrosine kinase (RTK) signaling, phenocopy many defects associated with 22q11DS in the mouse. The stepwise reduction of Sprouty gene dosage resulted in different phenotypes emerging at specific steps, suggesting that the threshold up to which a given developmental process can tolerate increased RTK signaling is different. Tbx1 heterozygosity significantly exacerbated the severity of all these defects, which correlated with a substantial increase in RTK signaling. CONCLUSIONS: Our findings suggest that TBX1 functions as an essential component of a mechanism that protects the embryo against perturbations in RTK signaling that may lead to developmental defects characteristic of 22q11DS. We propose that genetic factors that enhance RTK signaling ought to be considered as potential genetic modifiers of this syndrome.

Original publication

DOI

10.1002/dvdy.23812

Type

Journal article

Journal

Dev Dyn

Publication Date

08/2012

Volume

241

Pages

1310 - 1324

Keywords

Alleles, Animals, Gene Expression Regulation, Developmental, In Situ Hybridization, Magnetic Resonance Imaging, Mice, Mice, Knockout, Mice, Mutant Strains, Real-Time Polymerase Chain Reaction, Receptor Protein-Tyrosine Kinases, Signal Transduction, T-Box Domain Proteins