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Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice
Bing Lang, … , Anthony J. Harmar, Sanbing Shen
Bing Lang, … , Anthony J. Harmar, Sanbing Shen
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1924-1934. https://doi.org/10.1172/JCI27597.
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Research Article Neuroscience

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

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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 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

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

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Figure 6

Tg mice are defective in cortical lamination but less likely defective in axonal guidance.

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Tg mice are defective in cortical lamination but less likely defective i...
(A and B) Nissl staining of coronal brain sections of WT (inset, A) and Tg (inset, B) littermates revealed dilated ventricles. Magnified images of the boxed regions shown in the insets of A and B illustrate thinned cerebral cortex and cc. Note that layer V was significantly reduced, with fewer large neurons (pyramidal). (C) X-gal staining showed transgene expression largely at layers V and VI. (D and E) Glial fibrillary acidic protein (GFAP) immunostaining of brains of P1 WT mice (D) and Tg littermates (E) demonstrating a similar staining pattern at the glial wedge (black boxes) and the indusium griseum (arrows), magnified in the insets. Note that the thickness of cc (delineated by vertical lines) was also reduced in Tg newborns. F and G show magnification of the glial wedges delineated by the black boxes in D and E, revealing slightly more glial staining in Tg mice (G). Scale bars: 200 μm in A–E; 50 μm in F and G and insets of D and E; 1 mm in insets of A–C.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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