Functional Coupling between the Extracellular Matrix and Nuclear Lamina by Wnt Signaling in Progeria
Functional Coupling between the Extracellular Matrix and Nuclear Lamina by Wnt Signaling in Progeria
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DOI：
10.1016/j.devcel.2010.08.013
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发表时间：
2010-09-14
影响因子：
11.8
通讯作者：
Stewart, Colin L.
中科院分区：
文献类型：
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作者：
Hernandez, Lidia;Roux, Kyle J.;Stewart, Colin L.
节段性早衰症Hutchinson-Gilford Progeria（HGPS）是由核纤层蛋白A的截短和法尼基化形式引起的。在HGPS的小鼠模型中，类似的核纤层蛋白A变体导致出生后而不是胚胎成纤维细胞的增殖停滞和死亡。停滞是由于不能产生功能性细胞外基质（ECM），因为正常ECM上的生长挽救了增殖。这些缺陷与经典Wnt信号传导的抑制有关，这是由于在小鼠和人的早衰细胞中Lef 1的核定位和转录活性降低，而不是Tcf 4。缺陷Wnt信号传导，影响ECM合成，可能是HGPS的病因学的关键，因为小鼠表现出骨骼缺陷和心脏近端的主要血管凋亡。这些结果建立了核被膜/层和细胞表面/ECM之间的功能联系，并可能提供对Wnt信号传导和ECM在衰老中的作用的见解。
The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/ lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging.