Dept of Chemistry and Biology, University of Salerno, Italy.
Institute of Genetics and Biophysics, CNR, Naples, Italy.
Biochem Biophys Res Commun. 2024 Aug 6;720:150104. doi: 10.1016/j.bbrc.2024.150104. Epub 2024 May 13.
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.
T-BOX 转录因子 TBX1 对于咽器的发育是必不可少的，它在 DiGeorge 综合征（DGS）中表现为杂合不足，DGS 是一种与先天性心脏病和其他异常相关的发育异常。鼠模型重现了心脏表型，并显示出胶原蛋白的积累。我们首先使用细胞模型研究了 WT 和 Tbx1 小鼠胚胎干细胞在心脏发生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，在心脏前体细胞分化模型中丢失 Tbx1 与一组细胞外基质（ECM）相关基因的上调有关，包括几个胶原蛋白基因。在体内模型中，米诺地尔（一种赖氨酰羟化酶抑制剂）的早期产前治疗改善了 Tbx1 突变型胎儿的流出道隔室化表型，但对 WT 胎儿的隔室化没有影响。我们得出结论，TBX1 抑制了一组特定的 ECM 相关基因。该功能对于 OFT 隔室化至关重要，因为突变体中胶原蛋白交联的抑制显著降低了隔室化缺陷的发生率。
