title: Phenotype analysis of male transgenic mice overexpressing mutant IGFBP-2 lacking the Cardin-Weintraub sequence motif: Reduced expression of synaptic markers and myelin basic protein in the brain and a lower degree of anxiety-like behaviour.
abstract: Brain growth and function are regulated by insulin-like growth factors I and II (IGF-I and IGF-II) but also by IGF-binding proteins (IGFBPs), including IGFBP-2. In addition to modulating IGF activities, IGFBP-2 interacts with a number of components of the extracellular matrix and cell membrane via a Cardin-Weintraub sequence or heparin binding domain (HBD1). The nature and the signalling elicited by these interactions are not fully understood. Here, we examined transgenic mice (H1d-hBP2) overexpressing a mutant human IGFBP-2 that lacks a specific heparin binding domain (HBD1) known as the Cardin-Weintraub sequence. H1d-hBP2 transgenic mice have the genetic background of FVB mice and are characterized by severe deficits in brain growth throughout their lifetime (p<0.05). In tissue lysates from brain hemispheres of 12-21day old male mice, protein levels of the GTPase dynamin-I were significantly reduced (p<0.01). Weight reductions were also found in distinct brain regions in two different age groups (12 and 80weeks). In the younger group, impaired weights were observed in the hippocampus (-34%; p<0.001), cerebellum (-25%; p<0.0001), olfactory bulb (-31%; p<0.05) and prefrontal cortex (-29%; p<0.05). At an age of 12weeks expression of myelin basic protein was reduced (p<0.01) in H1d-BP-2 mice in the cerebellum but not in the hippocampus. At 80weeks of age, weight reductions were similarly present in the cerebellum (-28%; p<0.001) and hippocampus (-31; p<0.05). When mice were challenged in the elevated plus maze, aged but not younger H1d-hBP2 mice displayed significantly less anxiety-like behaviour, which was also observed in a second transgenic mouse model overexpressing mouse IGFBP-2 lacking HBD1 (H1d-mBP2). These in vivo studies provide, for the first time, evidence for a specific role of IGFBP-2 in brain functions associated with anxiety and risk behaviour. These activities of IGFBP-2 could be mediated by the Cardin-Weintraub/HBD1 sequence and are altered in mice expressing IGFBP-2 lacking the HBD1.
authors.affiliation: Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Schindler
authors.affiliation: Oscar Langendorff Institute of Physiology, University of Rostock, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Mayer
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, DTA CNS, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Saenger
authors.affiliation: Institute of Behavioural Physiology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Gimsa
authors.affiliation: Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Walz
authors.affiliation: Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Brenmoehl
authors.affiliation: Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Ohde
authors.affiliation: Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Wirthgen
authors.affiliation: Institute of Genetic and Biometry, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Tuchscherer
authors.affiliation: Hormone Research, Murdoch Childrens Research Institute, University of Melbourne, Australia.
authors.forename: V C
authors.initials: VC
authors.lastname: Russo
authors.affiliation: Medical Biology and Electron Microscopy Centre, University Medicine Rostock, Rostock, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Frank
authors.affiliation: Oscar Langendorff Institute of Physiology, University of Rostock, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kirschstein
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Pharma Research & Early Development, DTA CNS, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Metzger
authors.affiliation: Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany. Electronic address: hoeflich@fbn-dummerstorf.de.
authors.forename: A
authors.initials: A
authors.lastname: Hoeflich
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001007:Anxiety / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism*; D010641:Phenotype; D017384:Sequence Deletion; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C406407:DEFB1 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D004676:Myelin Basic Protein; D023083:beta-Defensins
keywords: Elevated plus maze; Heparin binding domain; IGFBP-2; Mouse brain; Myelin; Synaptic marker