TY - JOUR
T1 - Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency
AU - Barnhoorn, Sander
AU - Uittenboogaard, Lieneke M
AU - Jaarsma, Dick
AU - Vermeij, Wilbert P
AU - Tresini, Maria
AU - Weymaere, Michael
AU - Menoni, Hervé
AU - Brandt, Renata M C
AU - de Waard, Monique C
AU - Botter, Sander M
AU - Sarker, Altaf H
AU - Jaspers, Nicolaas G J
AU - van der Horst, Gijsbertus T J
AU - Cooper, Priscilla K
AU - Hoeijmakers, Jan H J
AU - van der Pluijm, Ingrid
N1 - Publisher Copyright:
© 2014, Public Library of Science. All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg−/− mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.
AB - As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg−/− mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.
KW - Aging/genetics
KW - Animals
KW - Brain/pathology
KW - Cachexia/etiology
KW - Central Nervous System/physiology
KW - DNA Repair/genetics
KW - DNA-Binding Proteins/deficiency
KW - Deficiency Diseases/etiology
KW - Disease Models, Animal
KW - Endonucleases/deficiency
KW - Female
KW - Liver/pathology
KW - Longevity/genetics
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Nuclear Proteins/deficiency
KW - Osteoporosis/etiology
KW - Pregnancy
KW - Transcription Factors/deficiency
UR - https://www.mendeley.com/catalogue/c9436020-9973-3ce3-8662-cf7dbe23c76e/
U2 - 10.1371/journal.pgen.1004686
DO - 10.1371/journal.pgen.1004686
M3 - Article
C2 - 25299392
SN - 1553-7390
VL - 10
SP - e1004686
JO - PLoS genetics
JF - PLoS genetics
IS - 10
ER -