Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling.
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.
Department of Craniofacial Development and Stem Cell Biology, King's College London, Guy's Tower, London, United Kingdom.
Subreena
S
Simrick
Dorota
D
Szumska
Jennifer R
JR
Gardiner
Kieran
K
Jones
Karun
K
Sagar
Bernice
B
Morrow
Shoumo
S
Bhattacharya
M Albert
MA
Basson
D000483:Alleles; D000818:Animals; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D017403:In Situ Hybridization; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases