Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria.
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 postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because 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, may be critical to the etiology of HGPS because 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.
Hernandez
Lidia
L
Cancer and Developmental Biology Laboratory, NCI, Frederick, MD 21702, USA.
Roux
Kyle J
KJ
Wong
Esther Sook Miin
ES
Mounkes
Leslie C
LC
Mutalif
Rafidah
R
Navasankari
Raju
R
Rai
Bina
B
Cool
Simon
S
Jeong
Jae-Wook
JW
Wang
Honghe
H
Lee
Hyun-Shik
HS
Kozlov
Serguei
S
Grunert
Martin
M
Keeble
Thomas
T
Jones
C Michael
CM
Meta
Margarita D
MD
Young
Stephen G
SG
Daar
Ira O
IO
Burke
Brian
B
Perantoni
Alan O
AO
Stewart
Colin L
CL
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D034904:Lamin Type A / Q000502:physiology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034881:Nuclear Lamina / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011371:Progeria / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013577:Syndrome; D051153:Wnt Proteins / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology*
D015415:Biomarkers; D034904:Lamin Type A; D012333:RNA, Messenger; D051153:Wnt Proteins; D008156:Luciferases