Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice

摘要: Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, its relationship with G protein–coupled receptors (GPCRs) unknown. We have expressed 2, 4, or 6 copies of GPCR — human PAC1 receptor 130-kb transgene in mouse nervous system pattern closely resembling that endogenous gene. Consistent actions, PKA PKC activity were elevated brains Tg mice. Remarkably, mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third lateral ventricles reduced cerebral cortex, corpus callosum, subcommissural organ (SCO). Neuronal proliferation apoptosis implicated hydrocephalus, we observed significantly neuronal massively increased developing cortex SCO embryos, while neurite outgrowth migration vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, ependyma exhibited disrupted phospho-CREB immunoreactivity. These data demonstrate altered proliferation/apoptosis main factors contributing to hydrocephalus PAC1-overexpressing This first report our knowledge demonstrating misregulation GPCRs can be involved hydrocephalus-related neurodevelopmental disorders.