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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Hydrocephalus
Cilia
Subcommissural Organ
G-Protein-Coupled Receptors
Apoptosis
Ependyma
Third Ventricle
Corpus Callosum
Lateral Ventricles
Transgenes
Cerebral Cortex
Nervous System
Cerebrospinal Fluid
Embryonic Structures
Brain
Genes

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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Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice. / Lang, Bing; Song, Bing; Davidson, Wendy; MacKenzie, Alasdair; Smith, Norman; McCaig, Colin D.; Harmar, Anthony J.; Shen, Sanbing.

In: The Journal of Clinical Investigation, Vol. 116, No. 7, 03.07.2006, p. 1924-1934.

Research output: Contribution to journalArticle

Lang, Bing ; Song, Bing ; Davidson, Wendy ; MacKenzie, Alasdair ; Smith, Norman ; McCaig, Colin D. ; Harmar, Anthony J. ; Shen, Sanbing. / Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice. In: The Journal of Clinical Investigation. 2006 ; Vol. 116, No. 7. pp. 1924-1934.
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