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PMID:19744960

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Citation

Giovannone, B, Tsiaras, WG, de la Monte, S, Klysik, J, Lautier, C, Karashchuk, G, Goldwurm, S and Smith, RJ (2009) GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling. Hum. Mol. Genet. 18:4629-39

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.

Links

PubMed PMC2773276 Online version:10.1093/hmg/ddp430

Keywords

Animals; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cells, Cultured; Disease Models, Animal; Female; Fibroblasts/metabolism; Gene Silencing; Humans; Insulin-Like Growth Factor I/genetics; Insulin-Like Growth Factor I/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 3/genetics; Mitogen-Activated Protein Kinase 3/metabolism; Motor Activity; Nerve Degeneration/embryology; Nerve Degeneration/genetics; Nerve Degeneration/metabolism; Nerve Degeneration/physiopathology; Receptor, IGF Type 1/genetics; Receptor, IGF Type 1/metabolism; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:IGF1

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:INSR

acts_upstream_of_or_within

GO:0071363: cellular response to growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:AKT1

acts_upstream_of_or_within

GO:0071363: cellular response to growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0021522: spinal cord motor neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0008344: adult locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0007631: feeding behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0031571: mitotic G1 DNA damage checkpoint signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0009791: post-embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0050885: neuromuscular process controlling balance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0050881: musculoskeletal movement

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0048873: homeostasis of number of cells within a tissue

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0048009: insulin-like growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0044267: cellular protein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:GGYF2

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4126459

P

Seeded From UniProt

complete

MOUSE:INSR

acts_upstream_of_or_within

GO:0071363: cellular response to growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:AKT1

acts_upstream_of_or_within

GO:0071363: cellular response to growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete


See also

References

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