title: Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice.
abstract: Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein-coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR--the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endogenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PAC1-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, and Ultrasound Department, Aberdeen Maternity Hospital, Grampian University Hospitals NHS Trust, Aberdeen, United Kingdom.
authors.forename: Bing
authors.initials: B
authors.lastname: Lang
authors.forename: Bing
authors.initials: B
authors.lastname: Song
authors.forename: Wendy
authors.initials: W
authors.lastname: Davidson
authors.forename: Alastair
authors.initials: A
authors.lastname: MacKenzie
authors.forename: Norman
authors.initials: N
authors.lastname: Smith
authors.forename: Colin D
authors.initials: CD
authors.lastname: McCaig
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Harmar
authors.forename: Sanbing
authors.initials: S
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism; D004805:Ependyma / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D006801:Humans; D006849:Hydrocephalus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I