Accumulation of progerin affects the symmetry of cell division and is associated with impaired Wnt signaling and the mislocalization of nuclear envelope proteins

Agustín Sola-Carvajal, Gwladys Revêchon, Hafdis T. Helgadottir, Daniel Whisenant, Robin Hagblom, Julia Döhla, Pekka Katajisto, David Brodin, Fredrik Fagerström-Billai, Nikenza Viceconte, Maria Eriksson

Research output: Contribution to journalArticleScientificpeer-review

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 stem cells ability 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/β-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of β-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.
Original languageEnglish
JournalJournal of Investigative Dermatology
ISSN0022-202X
DOIs
Publication statusPublished - 23 Apr 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine

Cite this

Sola-Carvajal, Agustín ; Revêchon, Gwladys ; Helgadottir, Hafdis T. ; Whisenant, Daniel ; Hagblom, Robin ; Döhla, Julia ; Katajisto, Pekka ; Brodin, David ; Fagerström-Billai, Fredrik ; Viceconte, Nikenza ; Eriksson, Maria. / Accumulation of progerin affects the symmetry of cell division and is associated with impaired Wnt signaling and the mislocalization of nuclear envelope proteins. In: Journal of Investigative Dermatology. 2019.
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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 stem cells ability 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/β-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of β-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.",
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Accumulation of progerin affects the symmetry of cell division and is associated with impaired Wnt signaling and the mislocalization of nuclear envelope proteins. / Sola-Carvajal, Agustín; Revêchon, Gwladys; Helgadottir, Hafdis T.; Whisenant, Daniel; Hagblom, Robin; Döhla, Julia; Katajisto, Pekka; Brodin, David; Fagerström-Billai, Fredrik; Viceconte, Nikenza; Eriksson, Maria.

In: Journal of Investigative Dermatology, 23.04.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Accumulation of progerin affects the symmetry of cell division and is associated with impaired Wnt signaling and the mislocalization of nuclear envelope proteins

AU - Sola-Carvajal, Agustín

AU - Revêchon, Gwladys

AU - Helgadottir, Hafdis T.

AU - Whisenant, Daniel

AU - Hagblom, Robin

AU - Döhla, Julia

AU - Katajisto, Pekka

AU - Brodin, David

AU - Fagerström-Billai, Fredrik

AU - Viceconte, Nikenza

AU - Eriksson, Maria

PY - 2019/4/23

Y1 - 2019/4/23

N2 - 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 stem cells ability 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/β-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of β-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.

AB - 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 stem cells ability 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/β-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of β-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.

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DO - 10.1016/j.jid.2019.05.005

M3 - Article

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

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