Document Detail


Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling.
MedLine Citation:
PMID:  22674535     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Subreena Simrick; Dorota Szumska; Jennifer R Gardiner; Kieran Jones; Karun Sagar; Bernice Morrow; Shoumo Bhattacharya; M Albert Basson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-26
Journal Detail:
Title:  Developmental dynamics : an official publication of the American Association of Anatomists     Volume:  241     ISSN:  1097-0177     ISO Abbreviation:  Dev. Dyn.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-18     Completed Date:  2012-11-28     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  9201927     Medline TA:  Dev Dyn     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1310-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Animals
Gene Expression Regulation, Developmental / genetics,  physiology
In Situ Hybridization
Magnetic Resonance Imaging
Mice
Mice, Knockout
Mice, Mutant Strains
Real-Time Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases / genetics,  metabolism*
Signal Transduction
T-Box Domain Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
090532//Wellcome Trust; CH/09/003//British Heart Foundation; G0601104//Medical Research Council; P01 HD070454/HD/NICHD NIH HHS; P01 HD070454/HD/NICHD NIH HHS; R01 DC005186/DC/NIDCD NIH HHS; R01 HL084410/HL/NHLBI NIH HHS; R01 HL088698/HL/NHLBI NIH HHS; R01 HL088698/HL/NHLBI NIH HHS; R21 NS065441/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/T-Box Domain Proteins; 0/Tbx1 protein, mouse; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases
Comments/Corrections

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