Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, Floor 27, Guy's Tower, London SE1 9RT, UK.
Comparative Biomedical Sciences, Royal Veterinary College, Camden, London, NW1 0TU, UK.
Development. 2019 Jul 29;146(14):dev176776. doi: 10.1242/dev.176776.
In human, mutations of the protocadherins FAT4 and DCHS1 result in Van Maldergem syndrome, which is characterised, in part, by craniofacial abnormalities. Here, we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation in mouse. We show that and mutants mimic the craniofacial phenotype of the human syndrome and that Dchs1-Fat4 signalling is essential for osteoblast differentiation. In mutants, proliferation of osteoprogenitors is increased and osteoblast differentiation is delayed. We show that loss of Dchs1-Fat4 signalling is linked to increased Yap-Tead activity and that Yap is expressed and required for proliferation in osteoprogenitors. In contrast, Taz is expressed in more-committed Runx2-expressing osteoblasts, Taz does not regulate osteoblast proliferation and Taz-Tead activity is unaffected in / mutants. Finally, we show that Yap and Taz differentially regulate the transcriptional activity of Runx2, and that the activity of Yap-Runx2 and Taz-Runx2 complexes is altered in / mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a signalling pathway in osteoblast differentiation, reveal its crucial role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.
在人类中，原钙黏蛋白 FAT4 和 DCHS1 的突变导致范马尔代格姆综合征，其部分特征是颅面异常。在这里，我们分析了 Dchs1-Fat4 信号在小鼠成骨细胞分化中的作用。我们表明 和 突变体模拟了人类综合征的颅面表型，并且 Dchs1-Fat4 信号对于成骨细胞分化是必不可少的。在 突变体中，成骨前体细胞的增殖增加，成骨细胞分化延迟。我们表明，Dchs1-Fat4 信号的丧失与 Yap-Tead 活性的增加有关，并且 Yap 在成骨前体细胞的增殖中表达并需要 Yap。相比之下，Taz 在更具分化能力的 Runx2 表达的成骨细胞中表达，Taz 不调节成骨细胞增殖，并且 / 突变体中的 Taz-Tead 活性不受影响。最后，我们表明 Yap 和 Taz 差异调节 Runx2 的转录活性，并且 Yap-Runx2 和 Taz-Runx2 复合物的活性在 / 突变体成骨细胞中发生改变。总之，这些数据将 Dchs1-Fat4 确定为成骨细胞分化中的信号通路，揭示了其在早期 Runx2 祖细胞中的关键作用，并确定了 Yap 和 Taz 在成骨细胞分化过程中的不同要求。
