XB-ART-42278Dev Cell 2010 Sep 14;193:413-25. doi: 10.1016/j.devcel.2010.08.013.
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Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria.
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.
PubMed ID: 20833363
PMC ID: PMC2953243
Article link: Dev Cell
Species referenced: Xenopus laevis
Genes referenced: lef1 lmna robo3 tcf4 wnt3a
GO keywords: extracellular matrix
Antibodies: Lmna Ab1 Tcf3 Ab3
Disease Ontology terms: progeria
OMIMs: HUTCHINSON-GILFORD PROGERIA SYNDROME; HGPS
Article Images: [+] show captions
|Figure 5. δ9 and δ50 Lamin Inhibit Wnt-Mediated Transcription(A) TOPflash/FOPflash luciferase reporter assays with WT (BC), δ9, δ50 lamins, or their SSIM variants.(B) Gst-Tcf pull-down of nuclear β-catenin levels.(C) Injection of Xwnt3a mRNA into Xenopus embryos, alone or in the presence of each LMNA construct shown in (A) and (B). Lower panel, western analysis shows amount of protein derived from the different LMNA mRNAs injected.Error bars are SEM.|
References [+] :
Adams, Regulation of development and differentiation by the extracellular matrix. 1993, Pubmed