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

Bing Lang, Bing Song, Wendy Davidson, Alasdair MacKenzie, Norman Smith, Colin D. McCaig, Anthony J. Harmar, Sanbing Shen

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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 endovenous 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 PACl-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)1924-1934
Number of pages11
JournalThe Journal of Clinical Investigation
Volume116
Issue number7
DOIs
Publication statusPublished - 3 Jul 2006

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Keywords

  • Animals
  • Apoptosis
  • Brain
  • Cell Movement
  • Cell Proliferation
  • Cilia
  • Ependyma
  • Gene Dosage
  • Humans
  • Hydrocephalus
  • Mice
  • Mice, Transgenic
  • Neurons
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Protein Processing, Post-Translational
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I

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