Gao Yan, Walker Jemma Victoria, Tredwin Christopher, Hu Bing
Stem Cells & Regenerative Medicine Laboratory, Peninsula Dental School, Faculty of Health, University of Plymouth, 16 Research Way, Plymouth, PL6 8BU UK.
Curr Med (Cham). 2022;1(1):7. doi: 10.1007/s44194-022-00007-w. Epub 2022 May 26.
Crosstalk between different signalling pathways provide deep insights for how molecules play synergistic roles in developmental and pathological conditions. RBP-Jkappa is the key effector of the canonical Notch pathway. Previously we have identified that Wnt5a, a conventional non-canonical Wnt pathway member, was under the direct transcriptional control of RBP-Jkappa in dermal papilla cells. In this study we further extended this regulation axis to the other two kind of skeletal cells: chondrocytes and osteoblasts. Mice with conditional mesenchymal deletion of RBP-Jkappa developed Rickets like symptoms. Molecular analysis suggested local defects of Wnt5a expression in chondrocytes and osteoblasts at both mRNA and protein levels, which impeded chondrocyte and osteoblast differentiation. The defects existing in the RBP-Jkappa deficient mutants could be rescued by recombinant Wnt5a treatment at both cellular level and tissue/organ level. Our results therefore provide a model of studying the connection of Notch and Wnt5a pathways with Rickets.
The online version contains supplementary material available at 10.1007/s44194-022-00007-w.
不同信号通路之间的串扰为分子如何在发育和病理条件下起协同作用提供了深刻见解。RBP-Jκ是经典Notch信号通路的关键效应器。此前我们已确定，传统非经典Wnt信号通路成员Wnt5a在真皮乳头细胞中受RBP-Jκ的直接转录调控。在本研究中，我们进一步将这一调控轴扩展至另外两种骨骼细胞：软骨细胞和成骨细胞。条件性间充质RBP-Jκ缺失的小鼠出现了类似佝偻病的症状。分子分析表明，软骨细胞和成骨细胞中Wnt5a在mRNA和蛋白质水平均存在局部表达缺陷，这阻碍了软骨细胞和成骨细胞的分化。RBP-Jκ缺陷突变体中存在的缺陷可通过重组Wnt5a在细胞水平和组织/器官水平的处理得到挽救。因此，我们的结果提供了一个研究Notch和Wnt5a信号通路与佝偻病之间联系的模型。
在线版本包含可在10.1007/s44194-022-00007-w获取的补充材料。
