Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice

Abstract

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.

Dopamine D2 Receptor-mediated Epidermal Growth Factor Receptor Transactivation through a Disintegrin and Metalloprotease Regulates Dopaminergic Neuron Development via Extracellular Signal-related Kinase Activation

“…In conditional knock-out mice in which HB-EGF is reduced in the ventral forebrain, prefrontal cortex dopamine levels are significantly lower than in control mice (21), and these knock-out mice display behavioral abnormalities associated with psychiatric disorders. These reports suggest that HB-EGF signaling plays an important role within the dopaminergic system.…”

Role of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Light-Induced Photoreceptor Degeneration in Mouse Retina

“…HB-EGF KO mice were generated using the Cre-lox-mediated conditional gene KO approach with a Six3 promoter as described previously. 36 Because they are associated with cardiac enlargement, HB-EGF KO mice died. 37 Six3 plays an important role in vertebrate visual system development.…”

The involvement of <italic>N</italic>-methyl-d-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia

“…A multiplatform profiling study identified peripheral changes that are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction [122]. Besides the abnormal behaviors similar to those described in other schizophrenia mouse model [123], reduction of NR1 subunits was observed in mice with heparin-binding epidermal growth factor (HB-EGF) disruption. Additionally, NR1 subunits were considered as mediators of reduced Specificity Protein (Sp) transcription factors associated with negative symptoms in schizophrenia.…”