title: Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria.
abstract: 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.
authors.affiliation: Cancer and Developmental Biology Laboratory, NCI, Frederick, MD 21702, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Hernandez
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Roux
authors.forename: Esther Sook Miin
authors.initials: ES
authors.lastname: Wong
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Mounkes
authors.forename: Rafidah
authors.initials: R
authors.lastname: Mutalif
authors.forename: Raju
authors.initials: R
authors.lastname: Navasankari
authors.forename: Bina
authors.initials: B
authors.lastname: Rai
authors.forename: Simon
authors.initials: S
authors.lastname: Cool
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.forename: Honghe
authors.initials: H
authors.lastname: Wang
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Martin
authors.initials: M
authors.lastname: Grunert
authors.forename: Thomas
authors.initials: T
authors.lastname: Keeble
authors.forename: C Michael
authors.initials: CM
authors.lastname: Jones
authors.forename: Margarita D
authors.initials: MD
authors.lastname: Meta
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Ira O
authors.initials: IO
authors.lastname: Daar
authors.forename: Brian
authors.initials: B
authors.lastname: Burke
authors.forename: Alan O
authors.initials: AO
authors.lastname: Perantoni
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
mesh_terms: 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*
chemical_list: D015415:Biomarkers; D034904:Lamin Type A; D012333:RNA, Messenger; D051153:Wnt Proteins; D008156:Luciferases