Functional Coupling between the Extracellular Matrix and Nuclear Lamina by Wnt Signaling in Progeria

Abstract

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 post-natal but not embryonic fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), as 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, maybe critical to the etiology of HGPS as 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.

Biological aging alters circadian mechanisms in murine adipose tissue depots

“…Since adipocyte hypertrophy is an indicator of insulin resistance, it can be used to predict risk of type 2 diabetes mellitus (Yang et al 2004). Recent studies have determined that the nuclear membrane protein, lamin, mediates the canonical Wnt signal transduction pathway via β-catenin and the Tcf/Lef transcription factor (Hernandez et al 2010). This work used a lamin mutant murine model which displays age-dependent subcutaneous adipose fat loss as well as the cranial and skeletal pathologies and the reduced longevity characteristic of Hutchinson-Gifford progeria syndrome (Hernandez et al 2010).…”

“…Recent studies have determined that the nuclear membrane protein, lamin, mediates the canonical Wnt signal transduction pathway via β-catenin and the Tcf/Lef transcription factor (Hernandez et al 2010). This work used a lamin mutant murine model which displays age-dependent subcutaneous adipose fat loss as well as the cranial and skeletal pathologies and the reduced longevity characteristic of Hutchinson-Gifford progeria syndrome (Hernandez et al 2010). It is noteworthy that lamin gene mutations have been identified as causative in some patients with familial partial lipodystrophy (Garg and Agarwal 2009).…”

Nuclear lamins and laminopathies

“…Deficiency of ZMPSTE24 similarly causes alterations in Wnt signalling [102]. The Notch and Wnt signalling pathways are important in controlling stem cell proliferation and differentiation, hence stem cell dysfunction may be a pathogenic factor in progerias caused by alteration in A-type lamins [100][101][102]. Rapamycin has also been shown to improve abnormal phenotypes in cells from subjects with Hutchinson-Gilford progeria syndrome, suggesting that the mTOR signalling axis may be involved in pathophysiology [103].…”

“…Defective canonical Wnt signalling occurs in cells from mouse models of Hutchinson-Gilford progeria syndrome and affected human subjects [101]. Deficiency of ZMPSTE24 similarly causes alterations in Wnt signalling [102].…”

Dual Specificity Phosphatase 4 Mediates Cardiomyopathy Caused by Lamin A/C (LMNA) Gene Mutation

“…Recent evidence suggests that A-type lamins play a dynamic role in regulating signal transduction, particularly ERK1/2 signaling (1,(3)(4)(5). We previously showed that activated ERK1/2 in hearts of Lmna H222P/H222P mice, a mouse model of LMNA cardiomyopathy, contributes to disease (6 -8).…”