title: Signalling through the type 1 insulin-like growth factor receptor (IGF1R) interacts with canonical Wnt signalling to promote neural proliferation in developing brain.
abstract: Signalling through the IGF1R [type 1 IGF (insulin-like growth factor) receptor] and canonical Wnt signalling are two signalling pathways that play critical roles in regulating neural cell generation and growth. To determine whether the signalling through the IGF1R can interact with the canonical Wnt signalling pathway in neural cells in vivo, we studied mutant mice with altered IGF signalling. We found that in mice with blunted IGF1R expression specifically in nestin-expressing neural cells (IGF1RNestin-KO mice) the abundance of neural β-catenin was significantly reduced. Blunting IGF1R expression also markedly decreased: (i) the activity of a LacZ (β-galactosidase) reporter transgene that responds to Wnt nuclear signalling (LacZTCF reporter transgene) and (ii) the number of proliferating neural precursors. In contrast, overexpressing IGF-I (insulin-like growth factor I) in brain markedly increased the activity of the LacZTCF reporter transgene. Consistently, IGF-I treatment also markedly increased the activity of the LacZTCF reporter transgene in embryonic neuron cultures that are derived from LacZTCF Tg (transgenic) mice. Importantly, increasing the abundance of β-catenin in IGF1RNestin-KO embryonic brains by suppressing the activity of GSK3β (glycogen synthase kinase-3β) significantly alleviated the phenotypic changes induced by IGF1R deficiency. These phenotypic changes includes: (i) retarded brain growth, (ii) reduced precursor proliferation and (iii) decreased neuronal number. Our current data, consistent with our previous study of cultured oligodendrocytes, strongly support the concept that IGF signalling interacts with canonical Wnt signalling in the developing brain to promote neural proliferation. The interaction of IGF and canonical Wnt signalling plays an important role in normal brain development by promoting neural precursor proliferation.
authors.affiliation: *Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Qichen
authors.initials: Q
authors.lastname: Hu
authors.affiliation: †Seoul National University Boramae Medical Center, Seoul, Korea.
authors.forename: Seong Yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: ‡Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: John R
authors.initials: JR
authors.lastname: O'Kusky
authors.affiliation: *Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013844:Thiazoles; D051153:Wnt Proteins; D051176:beta Catenin; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D017526:Receptor, IGF Type 1; D001616:beta-Galactosidase; D018021:Lithium Chloride