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Accelerated Aging by Compromised Wnt Signaling

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Science Signaling  21 Sep 2010:
Vol. 3, Issue 140, pp. ec287
DOI: 10.1126/scisignal.3140ec287

Progeria is a rare disease caused by mutations in a protein, lamin A, that is part of the nuclear envelope. Patients with this disease are normal at birth but exhibit rapid aging (approximately aging 10 years for every year of life) and ultimately die in their early teens. Hernandez et al. continued the molecular characterization of the mutant protein that causes a mouse model of progeria and determined that, like the mutant protein (LMNAΔ50) that causes most cases of the human disease, the mutant mouse protein (LMNAΔ9) remained farnesylated and incorporated into the nuclear periphery. Wild-type lamin A is cleaved, and the farnesylation is removed during processing to the mature protein. In culture, the proliferative capacity of mouse embryo fibroblasts (MEFs) from the LMNAΔ9 animals or wild-type animals was identical, but when postnatal fibroblasts (MAFs) were compared, the LMNAΔ9 cells showed accelerated senescence and apoptosis. Microarray analysis for genes that were differentially expressed between LMNAΔ9 and wild-type MAFs revealed that one significantly affected group of genes was associated with the extracellular matrix (ECM). Indeed, plating the LMNAΔ9 MAFs on dishes that had been precoated with ECM secreted by wild-type MAFs allowed the LMNAΔ9 MAFs to grow for the same number of passages as wild-type cells and allowed the cells to grow to a higher density. This same rescue of proliferative capacity was not reproduced by growing the cells on plates coated with defined ECM components (fibronectin, collagen, laminin, thrombospondin, or Matrigel). Consistent with defects in ECM gene expression, the LMNAΔ9 mice had reduced bone density and increased bone fragility, as well as thinning of the vascular smooth muscle cell layer and increased numbers of apoptotic cells in the pulmonary artery. The defects in the skeleton, the presence of Wnt pathway genes in the microarray data, and the fact that several of the ECM genes are regulated by Wnt signaling suggested that Wnt signaling may be compromised in the LMNAΔ9 cells. Expression of the LMNAΔ9 construct in HEK293 (human embryonic kidney fibroblast cell line), along with a β-catenin reporter for Wnt activity, showed that the presence of LMNAΔ9 inhibited reporter gene expression, and a pull-down assay indicated that there was less nuclear Lef (the transcription factor that β-catenin binds to regulate gene expression) in LMNAΔ9-expressing cells. Chromatin immunoprecipitation assays with the LMNAΔ9 MAFs revealed that less Lef was bound to the Wnt-responsive Col11A1 gene, encoding a collagen. Nuclear extracts from two progeria patient cell lines also showed reduced abundance of Lef compared with a cell line from a normal individual. Treatment of LMNAΔ9 MAFs with a glycogen synthase kinase 3β inhibitor (GSK-3β is an inhibitor of the Wnt pathway) increased the binding of Lef to the Col11A1 gene and improved proliferative capacity and viability of the cells. These results suggest that targeting the Wnt pathway and GSK-3β, in particular, may be helpful for progeria patients; that Wnt signaling may be influenced by nuclear organization; and that altered nuclear lamin processing may contribute to some aspects of normal aging.

L. Hernandez, K. J. Roux, E. S. M. Wong, L. C. Mounkes, R. Mutalif, R. Navasankari, B. Rai, S. Cool, J.-W. Jeong, H. Wang, H.-S. Lee, S. Kozlov, M. Grunert, T. Keeble, C. M. Jones, M. D. Meta, S. G. Young, I. O. Daar, B. Burke, A. O. Perantoni, C. L. Stewart, Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria. Dev. Cell 19, 413–425 (2010). [PubMed]

A. Muchir, H. J. Worman, Signaling defects and the nuclear envelope in progeria. Dev. Cell 19, 355–356 (2010). [PubMed]

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