Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

Espada, Jesús; Varela, Ignacio; Flores, Ignacio; Ugalde, Alejandro P.; Cadiñanos, Juan; Pendás, Alberto M.; Stewart, Colin L.; Tryggvason, Karl; Blasco, María A.; Freije, José M. P.; López-Otı́n, Carlos

doi:10.1084/jem2054oia10

Cited by 36 publications

(54 citation statements)

References 18 publications

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“…In one study, microarray of Zmpste24 -/cells indicated upregulation of the p53 tumor suppressor pathway that may predispose HGPS fibroblasts to early senescence (Varela et al, 2005). The absence of ZMPSTE24-mediated cleavage of lamin A has also been linked to aberrant stem cell maintenance, a mechanism that may contribute to the defects observed in patients in tissues that rely heavily on stem cell niches, such as hair and skin (Espada et al, 2008;Scaffidi and Misteli, 2008). This might reflect an initial prosurvival strategy that eventually becomes detrimental to the cells and tissues.…”

Section: Potential Disease Mechanisms Resulting From a Lack Of Zmpstementioning

confidence: 99%

ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders

Barrowman

Michaelis

2009

BCHM

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ZMPSTE24 is an integral membrane zinc metalloprotease originally discovered in yeast as an enzyme (called Ste24p) required for maturation of the mating pheromone a-factor. Surprisingly, ZMPSTE24 has recently emerged as a key protease involved in human progeroid disorders. ZMPSTE24 has only one identified mammalian substrate, the precursor of the nuclear scaffold protein lamin A. ZMPSTE24 performs a critical endoproteolytic cleavage step that removes the hydrophobic farnesyl-modified tail of prelamin A. Failure to do so has drastic consequences for human health and longevity. Here, we discuss the discovery of the yeast and mammalian ZMPSTE24 orthologs and review the unexpected connection between ZMPSTE24 and premature aging.

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Section: Potential Disease Mechanisms Resulting From a Lack Of Zmpstementioning

confidence: 99%

ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders

Barrowman

Michaelis

2009

BCHM

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“…Together, these results are consistent with earlier studies where heterozygous Lef1 mice show diminished bone mass and those null for Lef1 are post-nataly growth retarded, have defective hair and tooth formation, tissues markedly affected in progeria (Noh et al, 2009; van Genderen et al, 1994). In addition, in Zmpste24 null mice, where Lamin A remains farnesylated, Wnt signaling is reduced in hair follicles (Espada et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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“…In support of this model, expression of progerin in skin cells resulted in impaired function and depletion of epidermal stem cells, as well as downregulation of both the Notch and Wnt signalling pathways [66]. Downregulation of the Wnt signalling pathway and accumulation of prelamin A were also observed in the hair follicle stem cells of Zmpste24‐deficient mice, leading to their reduced proliferation capacity [67]. Mice carrying the progeric mutation LMNAΔ9 show compromised extracellular matrix synthesis, which is caused by reduced function of LEF1 due to inhibition of the Wnt signalling pathway [68].…”

Section: Lamin a And Lamin C In Development And Organogenesismentioning

confidence: 99%

Lamins in development, tissue maintenance and stress

2012

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Lamins are nuclear intermediate filament proteins. They provide mechanical stability, organize chromatin and regulate transcription, replication, nuclear assembly and nuclear positioning. Recent studies provide new insights into the role of lamins in development, differentiation and tissue response to mechanical, reactive oxygen species and thermal stresses. These studies also propose the existence of separate filament networks for A-and B-type lamins and identify new roles for the different networks. Furthermore, they show changes in lamin composition in different cell types, propose explanations for the more than 14 distinct human diseases caused by lamin A and lamin C mutations and propose a role for lamin B1 in these diseases. Keywords: development; lamin; nuclear envelope; nuclear lamina; stress EMBO reports (2012) 13, 1070-1078; published online 13 November 2012; doi:10.1038/embor.2012 See the Glossary for abbreviations used in this article.Lamins are evolutionarily conserved nuclear intermediate filament proteins. They are restricted to the animal kingdom and are the main constituents of the nuclear lamina, which is a meshwork of lamins at the nuclear periphery and their associated proteins. Similarly to most intermediate filament proteins, lamins have a conserved α-helical coiled-coil rod domain flanked by variable amino-terminal head and carboxy-terminal tail domains [1]. The tail domain of lamins contains an immunoglobulin-like fold motif and a nuclear localization signal. Except for lamin C, all lamins are translated as prelamins with a C-terminal CaaX motif, which undergoes farnesylation. In Xenopus oocytes, lamins form filaments of about 10 nm in diameter, which are arranged in a regular, parallel pattern [2,3]. The basic building-block for higher-order lamin assembly is the lamin dimer. The first step in this assembly involves head-to-tail polymerization of the lamin dimers [4]. These polymers associate laterally in an antiparallel fashion to form the protofilament, and then between three and four protofilaments form the lamin filament [5]. However, the structure of lamin in somatic cells in vivo still needs to be determined. There is an uneven distribution of the lamin subtypes during development and throughout human tissues [6][7][8]. All somatic cell types, including embryonic stem cells (ESCs), express lamin B1 and/or lamin B2 (B-type lamins), which are encoded by LMNB1 and LMNB2 genes, respectively. Lamin A and lamin C are expressed from the LMNA gene through alternative splicing (A-type lamins), and differ from each other in their C-terminal tail domain. They are developmentally regulated and are not essential for somatic cell survival. Lamin A, lamin B1 and lamin B2 originate from prelamins. Their C-terminal CaaX motif undergoes farnesylation, aaX cleavage and carboxymethylation. Only lamin A is further cleaved 15 amino acids away from its farnesylated cysteine by the protease Zmpste24 [9]. Recent studies used fluorescence microscopy techniques in mammalian cells to show that A-type and B-t...

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Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

Abstract: Abbreviations used in this paper: 5mC, 5-methylcytosine; LRC, label-retaining cell; Mitf, microphthalmia transcription factor; TPA, tetradecanoylphorbol 13-acetate.

Cited by 36 publications

References 18 publications

ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders

ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders

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

Lamins in development, tissue maintenance and stress

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