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, characterised 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 homologue 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 mutations in two Sprouty genes, which encode feedback antagonists of receptor tyrosine kinase (RTK) signaling, phenocopy many defects associated with the syndrome 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 22q11.2 deletion syndrome. We propose that genetic factors that enhance RTK signalling ought to be considered as potential genetic modifiers of this syndrome.

Endoderm‐specific deletion of Tbx1 reveals an FGF‐independent role for Tbx1 in pharyngeal apparatus morphogenesis

“…E). This observation is in contrast to the severely reduced Spry1 and Spry2 expression in the pharyngeal region of Tbx1−/− embryos (Simrick et al, ). Taken together, these observations indicate that the near complete loss of Fgf8 expression in the endoderm of Tbx1cko embryos is not sufficient to cause an overall reduction in FGF signaling levels in the developing pharyngeal region at the time of caudal pouch formation.…”

“…Although previous studies have shown that the expression of several genes encoding FGF ligands are altered in Tbx1 ‐deficient embryos, few reports describe the effect these changes have on downstream FGF signaling (Vitelli et al, ; Simrick et al, ). Therefore, to determine whether the reduced expression of Fgf8 in the endoderm affected FGF signaling in the Tbx1cko pharyngeal apparatus, we analysed the expression of two transcriptional read‐outs of FGF signaling, Etv4 and Etv5 (Klein et al, ).…”

“…Taken together, these findings suggest that the mechanisms whereby Tbx1 in the endoderm controls caudal pouch formation are distinct from its effects on FGF signaling. Our recent demonstration that Tbx1 haplo-insufficiency can also affect the ability of the embryo to resist developmental alterations caused by increased FGF signaling, further suggest that the relation between Tbx1 and the FGF pathway may be more complex than originally anticipated (Simrick et al, 2012).…”

Early de novo DNA methylation and prolonged demethylation in the muscle lineage

“…Haploinsufficiency of TBX1 is responsible for most of the symptoms of the DiGeorge/velo-cardio-facial syndrome, the most common microdeletion syndrome in humans 65 , 66 . Symptoms include congenital heart and craniofacial abnormalities, skeletal muscle hypotonia, and increased risk of psychiatric disorders.…”

DNA Methylation and Differentiation: Silencing, Upregulation and Modulation of Gene Expression

“…Because they overlap a predicted region of enhancer activity in HMEC, one of the functions of this hypermethylation may be to prevent the formation of an interfering heterologous enhancer in myogenic cells (Figure 3C). TBX1 haploinsufficiency has been linked to most of the symptoms of the DiGeorge 22q11.2 deletion syndrome [75]. Therefore, DMRs may be needed for precise regulation of this cell type-specific and development stage-specific gene.…”