title: Insulin-like growth factor-I protects granule neurons from apoptosis and improves ataxia in weaver mice.
abstract: Most cerebellar granule neurons in weaver mice undergo premature apoptosis during the first 3 postnatal weeks, subsequently leading to severe ataxia. The death of these granule neurons appears to result from a point mutation in the GIRK2 gene, which encodes a G protein-activated, inwardly rectifying K+ channel protein. Although the genetic defect was identified, the molecular mechanism by which the mutant K+ channel selectively attacks granule neurons in weaver mice is unclear. Before their demise, weaver granule neurons express abnormally high levels of insulin-like growth factor (IGF) binding protein 5 (IGFBP5). IGF-I is essential for the survival of cerebellar neurons during their differentiation. Because IGFBP5 has the capacity to block IGF-I activity, we hypothesized that reduced IGF-I availability resulting from excess IGFBP5 accelerates the apoptosis of weaver granule neurons. We found that, consistently with this hypothesis, exogenous IGF-I partially protected cultured weaver granule neurons from apoptosis by activating Akt and decreasing caspase-3 activity. To determine whether IGF-I protects granule neurons in vivo, we cross-bred weaver mice with transgenic mice that overexpress IGF-I in the cerebellum. The cerebellar volume was increased in weaver mice carrying the IGF-I transgene, predominantly because of an increased number of surviving granule neurons. The presence of the IGF-I transgene resulted in improved muscle strength and a reduction in ataxia, indicating that the surviving granule neurons are functionally integrated into the cerebellar neuronal circuitry. These results confirm our previous suggestion that a lack of IGF-I activity contributes to apoptosis of weaver granule neurons in vivo and supports IGF-I's potential therapeutic use in neurodegenerative disease.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.forename: Jixian
authors.initials: J
authors.lastname: Deng
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phan
authors.forename: Stephen
authors.initials: S
authors.lastname: Dlouhy
authors.forename: Huangbing
authors.initials: H
authors.lastname: Wu
authors.forename: Weiguo
authors.initials: W
authors.lastname: Yao
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: D'Ercole
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001259:Ataxia / Q000473:pathology* / Q000503:physiopathology; D001522:Behavior, Animal; D001973:Bromodeoxyuridine; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002531:Cerebellum / Q000166:cytology*; D004256:DNA Polymerase I / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology
chemical_list: D007334:Insulin-Like Growth Factor I; D004256:DNA Polymerase I; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine