Department of Surgical Specialities, University of Messina, Italy.
Hum Mol Genet. 2011 Mar 1;20(5):1016-25. doi: 10.1093/hmg/ddq547. Epub 2010 Dec 20.
FOXE1 mutations cause the Bamforth-Lazarus syndrome characterized by thyroid and craniofacial defects. Although a pioneer activity of FOXE1 in thyroid development has been reported, FOXE1 regulation in other contexts remains unexplored. We pointed to: (i) a role of FOXE1 in controlling the expression of MSX1 and TGF-β3 relevant in craniofacial development and (ii) a causative part of FOXE1 mutations or mice Foxe1(-/-) genotype in the pathogenesis of cleft palate in the Bamforth-Lazarus syndrome. The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. Moreover, we showed that all the known forkhead-domain mutations, but not the polyalanine-stretch polymorphisms, affect the FOXE1 ability to bind to and transactivate MSX1 and TGF-β3 promoters. In 14-day Foxe1(-/-) mice embryos, Tgf-β3 and Msx1 mRNAs were almost absent in palatal shelves compared with Foxe1(+/-) embryos. Our findings give new insights into the genetic mechanisms underlying the Bamforth-Lazarus syndrome-associated facial defects.
FOXE1 突变导致 Bamforth-Lazarus 综合征，其特征为甲状腺和颅面缺陷。虽然 FOXE1 在甲状腺发育中的先驱活性已被报道，但 FOXE1 在其他情况下的调节仍未被探索。我们指出：(i)FOXE1 在控制颅面发育中相关的 MSX1 和 TGF-β3 的表达中的作用；(ii)FOXE1 突变或小鼠 Foxe1(-/-)基因型在 Bamforth-Lazarus 综合征中的腭裂发病机制中的致病作用。FOXE1 在转录和翻译水平上对 MSX1 和 TGF-β3 的上调，以及 FOXE1 与特定结合基序的募集，以及这些基因启动子的转录激活，表明 MSX1 和 TGF-β3 是 FOXE1 的直接靶标。此外，我们表明，所有已知的叉头结构域突变，但不是多聚丙氨酸延伸多态性，都会影响 FOXE1 结合和转录激活 MSX1 和 TGF-β3 启动子的能力。在 14 天的 Foxe1(-/-)小鼠胚胎中，与 Foxe1(+/-)胚胎相比，腭突中的 Tgf-β3 和 Msx1 mRNA 几乎不存在。我们的发现为 Bamforth-Lazarus 综合征相关面部缺陷的遗传机制提供了新的见解。
