Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling

Subreena Simrick, Dorota Szumska, Jennifer R. Gardiner, Kieran Jones, Karun Sagar, Bernice E. Morrow, Shoumo Bhattacharya, M. Albert Basson

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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. Developmental Dynamics 241:1310-1324, 2012.

Original languageEnglish (US)
Pages (from-to)1310-1324
Number of pages15
JournalDevelopmental Dynamics
Volume241
Issue number8
DOIs
StatePublished - Aug 2012

Fingerprint

DiGeorge Syndrome
Receptor Protein-Tyrosine Kinases
Embryonic Structures
Gene Dosage
Cleft Palate
Thoracic Aorta
Genes
Phenotype

Keywords

  • 22q11.2 deletion syndrome
  • Receptor tyrosine kinase signaling
  • Sprouty
  • Tbx1

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling. / Simrick, Subreena; Szumska, Dorota; Gardiner, Jennifer R.; Jones, Kieran; Sagar, Karun; Morrow, Bernice E.; Bhattacharya, Shoumo; Basson, M. Albert.

In: Developmental Dynamics, Vol. 241, No. 8, 08.2012, p. 1310-1324.

Research output: Contribution to journalArticle

Simrick, Subreena ; Szumska, Dorota ; Gardiner, Jennifer R. ; Jones, Kieran ; Sagar, Karun ; Morrow, Bernice E. ; Bhattacharya, Shoumo ; Basson, M. Albert. / Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling. In: Developmental Dynamics. 2012 ; Vol. 241, No. 8. pp. 1310-1324.
@article{cbfc9cc462304369a427519e02c72251,
title = "Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling",
abstract = "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. Developmental Dynamics 241:1310-1324, 2012.",
keywords = "22q11.2 deletion syndrome, Receptor tyrosine kinase signaling, Sprouty, Tbx1",
author = "Subreena Simrick and Dorota Szumska and Gardiner, {Jennifer R.} and Kieran Jones and Karun Sagar and Morrow, {Bernice E.} and Shoumo Bhattacharya and Basson, {M. Albert}",
year = "2012",
month = "8",
doi = "10.1002/dvdy.23812",
language = "English (US)",
volume = "241",
pages = "1310--1324",
journal = "Developmental Dynamics",
issn = "1058-8388",
publisher = "Wiley-Liss Inc.",
number = "8",

}

TY - JOUR

T1 - Biallelic expression of Tbx1 protects the embryo from developmental defects caused by increased receptor tyrosine kinase signaling

AU - Simrick, Subreena

AU - Szumska, Dorota

AU - Gardiner, Jennifer R.

AU - Jones, Kieran

AU - Sagar, Karun

AU - Morrow, Bernice E.

AU - Bhattacharya, Shoumo

AU - Basson, M. Albert

PY - 2012/8

Y1 - 2012/8

N2 - 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. Developmental Dynamics 241:1310-1324, 2012.

AB - 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. Developmental Dynamics 241:1310-1324, 2012.

KW - 22q11.2 deletion syndrome

KW - Receptor tyrosine kinase signaling

KW - Sprouty

KW - Tbx1

UR - http://www.scopus.com/inward/record.url?scp=84864008154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864008154&partnerID=8YFLogxK

U2 - 10.1002/dvdy.23812

DO - 10.1002/dvdy.23812

M3 - Article

VL - 241

SP - 1310

EP - 1324

JO - Developmental Dynamics

JF - Developmental Dynamics

SN - 1058-8388

IS - 8

ER -