T-BOX转录因子TBX1对于咽部的发育至关重要,并且在DiGeorge综合征(DGS)中单倍体不足,与先天性心脏病和其他异常相关的发育异常。鼠模型概括了心脏表型并显示胶原蛋白积累。我们首先使用细胞模型来研究WT和Tbx1-/-小鼠胚胎干细胞的心源性分化过程中的基因表达。然后,我们使用DGS的小鼠模型来测试使用赖氨酰羟化酶抑制剂干扰胶原蛋白积累是否会改变突变体的心脏表型。我们发现在心前分化模型中Tbx1的缺失与ECM相关基因子集的上调有关。包括几个胶原蛋白基因。在体内模型中,米诺地尔的早期产前治疗,赖氨酰羟化酶抑制剂,改善了Tbx1突变胎儿的心脏流出道间隔表型,但对WT胎儿的隔离没有影响。我们得出的结论是,TBX1抑制了ECM相关基因的定义子集。此功能对于OFT分隔至关重要,因为突变体中胶原蛋白交联的抑制显着降低了分隔缺陷的穿透率。
The T-BOX transcription factor
TBX1 is essential for the development of the pharyngeal apparatus and it is haploinsufficient in DiGeorge syndrome (DGS), a developmental anomaly associated with congenital heart disease and other abnormalities. The murine model recapitulates the heart phenotype and showed collagen accumulation. We first used a cellular model to study gene expression during cardiogenic differentiation of WT and
Tbx1-/- mouse embryonic stem cells. Then we used a mouse model of DGS to test whether interfering with collagen accumulation using an inhibitor of lysyl hydroxylase would modify the cardiac phenotype of the mutant. We found that loss of
Tbx1 in a precardiac differentiation model was associated with up regulation of a subset of ECM-related genes, including several collagen genes. In the in vivo model, early prenatal treatment with Minoxidil, a lysyl hydroxylase inhibitor, ameliorated the cardiac outflow tract septation phenotype in
Tbx1 mutant fetuses, but it had no effect on septation in WT fetuses. We conclude that
TBX1 suppresses a defined subset of ECM-related genes. This function is critical for OFT septation because the inhibition of collagen cross-linking in the mutant reduces significantly the penetrance of septation defects.