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Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice
Bing Lang1, Bing Song, Wendy Davidson
1School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, and Ultrasound Department, Aberdeen Maternity Hospital, Grampian University Hospitals NHS Trust, Aberdeen, United Kingdom.
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.
Insights
Altered expression of G protein-coupled receptors (GPCRs) can cause hydrocephalus. Overexpressing the PAC1 receptor in mice led to dose-dependent hydrocephalus-like features, impacting neuronal development and cilia function.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Hydrocephalus is a significant congenital central nervous system (CNS) defect.
- The role of G protein-coupled receptors (GPCRs) in hydrocephalus pathogenesis is largely unknown.
- PAC1 receptor is a specific type of GPCR involved in various cellular signaling pathways.
Purpose of the Study:
- To investigate the potential link between GPCRs, specifically the PAC1 receptor, and the development of hydrocephalus.
- To characterize the effects of PAC1 receptor overexpression on CNS development in a mouse model.
- To elucidate the underlying cellular mechanisms contributing to hydrocephalus in PAC1-overexpressing mice.
Main Methods:
- Generation of transgenic (Tg) mice with varying copies of the human PAC1 receptor transgene in the nervous system.
- Biochemical analysis of protein kinase A (PKA) and protein kinase C (PKC) activity in Tg mouse brains.
- Histological and immunohistochemical examination of brain structures, neuronal proliferation, apoptosis, and ependymal cilia in Tg embryos and mice.
- In vitro assessment of neurite outgrowth and neuronal migration.
Main Results:
- Transgenic mice exhibited dose-dependent hydrocephalus-like characteristics, including enlarged ventricles and reduced brain structures.
- Elevated PKA and PKC activity were observed in the brains of Tg mice.
- Significantly reduced neuronal proliferation and increased neuronal apoptosis were detected in the developing cortex and subcommissural organ (SCO) of Tg embryos.
- Disrupted ependymal cilia and increased phospho-CREB immunoreactivity were observed in the ventricles of Tg mice.
- Neurite outgrowth and neuronal migration were not compromised in vitro.
Conclusions:
- Overexpression of the PAC1 receptor can induce hydrocephalus in mice through mechanisms involving altered neuronal proliferation/apoptosis and disrupted ependymal cilia.
- This study provides the first evidence linking GPCR misregulation to hydrocephalus and related neurodevelopmental disorders.
- The findings highlight the critical role of PAC1 receptor signaling in normal brain development and cerebrospinal fluid dynamics.
