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

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 12-21 day 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 80 weeks). 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 12 weeks expression of myelin basic protein was reduced (p < 0.01) in H1d-BP-2 mice in the cerebellum but not in the hippocampus. At 80 weeks 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.