Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is the result of a defective form of the lamin A protein called progerin. While progerin is known to disrupt the properties of the nuclear lamina, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Previous studies in our laboratory have shown that progerin expression in murine epidermal basal cells results in impaired stratification and halted development of the skin. Stratification and differentiation of the epidermis is regulated by asymmetric stem cell division. Here, we show that expression of progerin impairs the ability of stem cells to maintain tissue homeostasis as a result of altered cell division. Quantification of basal skin cells showed an increase in symmetric cell division that correlated with progerin accumulation in HGPS mice. Investigation of the mechanisms underlying this phenomenon revealed a putative role of Wnt/b-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of b-catenin involving the inner and outer nuclear membrane proteins, emerin and nesprin-2. Taken together, our results suggest a direct involvement of progerin in the transmission of Wnt signaling and normal stem cell division. These insights into the molecular mechanisms of progerin may help develop new treatment strategies for HGPS.In situ hybridization K15 transcripts were detected using RNAscope (Advanced Cell Diagnostic, Newark, CA) in accordance with the manufacturer's protocol. Few modifications were made: target A Sola-Carvajal et al.

Towards delineating the chain of events that cause premature senescence in the accelerated aging syndrome Hutchinson–Gilford progeria (HGPS)

“…Nevertheless, the precise mechanism how progerin triggers this drastic change in chromatin compaction remains unclear. For instance, a recent transcriptional analysis of control versus progerin-expressing mouse skin found no significant changes in the expression of key epigenetic modulators [52], and expression of progerin in telomerase-positive cells did not result in any transcriptional changes [23].…”

From structural resilience to cell specification — Intermediate filaments as regulators of cell fate

“…186,187 The deformation has also been related to disrupted localization of nuclear pores, which may affect molecular trafficking to and from the nucleus and thereby perturb the communication between the nucleus and cytoplasm. 188 In addition, progerin also causes loss of peripheral heterochromatin and may therefore alter the gene expression profile. 187 Increased DNA damage, represented by γH2AX containing foci, is yet another consequence of cellular progerin accumulation.…”

“…73 In addition, vimentin may control cell fate specification by connecting extracellular mechanical cues with the intracellular transcriptional control machinery. 16 Similarly, nuclear lamins are essential in governing nuclear entry of certain signaling moieties 172,188 and presumably regulates nucleocytoplasmic shuttling of other transcription factors as well. Interestingly, keratins have also been found to shuttle in and out of the nucleus.…”

“…Progerin perturbs the structural integrity of the nucleus, resulting in deformation of the nuclear envelope 186,187 . The deformation has also been related to disrupted localization of nuclear pores, which may affect molecular trafficking to and from the nucleus and thereby perturb the communication between the nucleus and cytoplasm 188 . In addition, progerin also causes loss of peripheral heterochromatin and may therefore alter the gene expression profile 187 .…”

Drosophila female germline stem cells undergo mitosis without nuclear breakdown

“…30,31 Age-associated worsening of laminopathic diseases has been linked to failures in stem cell maintenance, 32,33 suggesting that the NL plays an important role in balancing stem cell proliferation with differentiation. Although contributions of the NL to stem cell function are being investigated, 12,[34][35][36] mechanisms that preserve healthy stem cell populations and promote tissue homeostasis remain poorly understood.…”