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 Morrow, Shoumo Bhattacharya, M. Albert Basson

Research output: Contribution to journalArticle

5 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Developmental Biology

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