title: Inhibition of insulin-like growth factor I activity contributes to the premature apoptosis of cerebellar granule neuron in weaver mutant mice: in vitro analysis.
abstract: Evidence from transgenic mice and cultured cerebellar neurons supports an important role for insulin-like growth factor I (IGF-I) in the formation of cerebellar cytoarchitecture. To understand IGF-I's function during cerebellar development, we examined the involvement of IGF-I in the premature apoptosis of granule neurons derived from the cerebella of weaver (wv) mutant mice. Before their demise, wv granule neurons increased the expression and secretion of IGFBP5 in a gene dose-dependent manner. Because IGFBP5 may interfere with the interaction of IGF-I and its receptor, the abnormally high IGFBP5 levels in wv granule neurons suggest that a lack of IGF-I activation may contribute to their premature apoptosis. This hypothesis is supported by a gene dose-dependent decrease in IGF-I receptor (IGF-IR) phosphorylation. More importantly, there is a parallel gene dose-dependent decrease in Akt activity, which was inversely correlated with the activity levels of caspase 3. On the other hand, adding IGFBP5 antibody into culture media increased the survival of wv granule neurons, whereas adding IGFBP5 decreased the survival of wild-type granule neurons. To delineate the interaction between IGF-I and IGFBP5 on wv granule neurons, we examined neuronal survival after treating with IGF-I, des(1-3) IGF-I, or IGFBP5 antibody. At the same concentration, des(1-3) IGF-I was more effective than IGF-I in promoting survival, in increasing Akt activity, and in decreasing caspase 3 activity. These results indicate that IGF-I's actions on wv granule neurons are normally inhibited by excess IGFBP5, and sufficient IGF-I receptor activation rescues wv granule neurons via stimulating the Akt signaling pathway.
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: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D005838:Genotype; D066298:In Vitro Techniques; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000378:metabolism*; D015513:Oncogene Proteins; D010766:Phosphorylation; D017354:Point Mutation; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; D015513:Oncogene Proteins; D015221:Potassium Channels; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse