title: GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling.
abstract: Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutations with Parkinson's disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2(+/-) mice survive to adulthood with no evident metabolic or growth defects. At 12-15 months of age, the Gigyf2(+/-) mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are alpha-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.
authors.affiliation: Division of Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Giovannone
authors.forename: William G
authors.initials: WG
authors.lastname: Tsiaras
authors.forename: Suzanne
authors.initials: S
authors.lastname: de la Monte
authors.forename: Jan
authors.initials: J
authors.lastname: Klysik
authors.forename: Corinne
authors.initials: C
authors.lastname: Lautier
authors.forename: Galina
authors.initials: G
authors.lastname: Karashchuk
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity; D009410:Nerve Degeneration / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; C547020:GIGYF2 protein, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D048052:Mitogen-Activated Protein Kinase 3