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

Luo, Bing; Song, Bing; Davidson, Wendy; Mackenzie, A. L.; Smith, N. Ty; McCaig, Colin; Harmar, Anthony J.; Shen, Sanbing

doi:10.1172/jci27597

Cited by 51 publications

(50 citation statements)

References 44 publications

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“…Primary neuronal culture was conducted as described previously (Lang et al, 2006). Briefly, 24-well plates were precoated with poly-L-ornithine (Sigma) for 1 h followed with fibronectin (Invitrogen) for 2 h. The newborns were genotyped by PCR.…”

Section: Methodsmentioning

confidence: 99%

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Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

Shen¹,

Luo²,

Nakamoto³

et al. 2008

J. Neurosci.

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239

204

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Disrupted-in-Schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated Disc1 tr transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. Disc1 tr transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in Disc1 tr transgenic mice are consistent with findings in severe schizophrenia.

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Section: Methodsmentioning

confidence: 99%

“…Sections were processed immunohistochemically as described previously (Lang et al, 2006). The primary antibodies included mouse anti-BrdU (1:200; BD Biosciences) and rabbit anti-parvalbumin (1:1500; Swant).…”

Section: Methodsmentioning

confidence: 99%

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

Shen¹,

Luo²,

Nakamoto³

et al. 2008

J. Neurosci.

Self Cite

239

204

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“…The present study has confirmed the involvement of cAMP in the control of ciliary function, as ACT was shown to significantly decrease ciliary amplitude. In line with these findings, mice overexpressing PAC1 receptor have been shown to have elevated PKA and PKC activity, ciliary defects and increased apoptosis, resulting in development of hydrocephalus (Lang et al, 2006).…”

Section: Discussionmentioning

confidence: 61%

“…Namely, PAC1 overexpressing mice showed a higher level of PAC1 expression especially in ventricle-surrounding regions, when compared to wild type (Lang et al, 2006). In the developing brain, PAC1 mRNA expression showed more intense subventricular localization (Basille et al, 2000;Jaworski and Proctor, 2000;Zhou et al, 1999) than in the adult (Hashimoto et al, 1996;Jaworski and Proctor, 2000;Shioda et al, 1997).…”

Section: Studies Onmentioning

confidence: 89%

“…The dual balance between G protein families G i and G s in the regulation of AC is well established, but G protein-coupled receptors have not been identified in CBF inhibition. Interestingly, a recent study showed that mice overexpressing PAC1 receptors developed hydrocephalus with excess activity of PKA pathway (Lang et al, 2006). PAC1 receptors are activated by pituitary adenylate cyclase-activating polypeptide (PACAP) and coupled to G s protein family.…”

Section: Introductionmentioning

confidence: 99%

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PACAP27 regulates ciliary function in primary cultures of rat brain ependymal cells

et al. 2008

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Ependymal cells line the brain ventricles and separate the CSF from the underlying neuronal tissue. The function of ependymal cilia is largely unclear however they are reported to be involved in the regulation of CSF homeostasis and host defence against pathogens. Here we present data that implicates a role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the inhibition of ependymal ciliary function, and also that the PACAP effects are not entirely dependent on adenylyl cyclase activation. Primary ependymal cultures were treated with increasing doses of PACAP27 or adenylyl cyclase toxin (ACT), and ciliary beating was recorded using high-speed digital video imaging. Ciliary beat frequency (CBF) and amplitude were determined from the videos. Ependymal CBF and ciliary amplitude were attenuated by PACAP27 in a concentration-and time-dependent manner. The peptide antagonist PACAP6-27 blocked PACAP27-induced decreases in amplitude and CBF.Treatment with ACT caused a decrease in amplitude but had no effect on CBF, this suggests that the inhibition of CBF and amplitude seen with PACAP27 may not be completely explained by G s -AC-cAMP pathway. We present here the first observational study to show that activation of PAC1 receptors with PACAP27 has an important role to play in the regulation of ependymal ciliary function.

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Ulk4 deficiency leads to hypomyelination in mice

Liu

Guan

et al. 2017

Glia

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Brain nerve fibers are insulated by myelin which is produced by oligodendrocytes. Defects in myelination are increasingly recognized as a common pathology underlying neuropsychiatric and neurodevelopmental disorders, which are associated with deletions of the Unc-51-like kinase 4 (ULK4) gene. Key transcription factors have been identified for oligodendrogenesis, but little is known about their associated regulators. Here we report that Ulk4 acts as a key regulator of myelination. Myelination is reduced by half in the Ulk4 tm1a/tm1a hypomorph brain, whereas expression of axonal marker genes Tubb3, Nefh, Nefl and Nefm remains unaltered. Transcriptome analyses reveal that 8 (Gfap, Mbp, Mobp, Plp1, Slc1a2, Ttr, Cnp, Scd2) of the 10 most significantly altered genes in the Ulk4 tm1a/tm1a brain are myelination-related. Ulk4 is co-expressed in Olig2 1 (pan-oligodendrocyte marker) and CC1 1 (mature myelinated oligodendrocyte marker) cells during postnatal development.Major oligodendrogeneic transcription factors, including Olig2, Olig1, Myrf, Sox10, Sox8, Sox6, Sox17, Nkx2-2, Nkx6-2 and Carhsp1, are significantly downregulated in the mutants. mRNA transcripts enriched in oligodendrocyte progenitor cells (OPCs), the newly formed oligodendrocytes (NFOs) and myelinating oligodendrocytes (MOs), are significantly attenuated. Expression of stage-specific oligodendrocyte factors including Cspg4, Sox17, Nfasc, Enpp6, Sirt2, Cnp, Plp1, Mbp, Ugt8, Mag and Mog are markedly decreased. Indirect effects of axon caliber and neuroinflammation may also contribute to the hypomyelination, as Ulk4 mutants display smaller axons and increased neuroinflammation. This is the first evidence demonstrating that ULK4 is a crucial regulator of myelination, and ULK4 may therefore become a novel therapeutic target for hypomyelination diseases. K E Y W O R D Shypomyelination, knockout mice, oligodendrogenesis, Ulk4, white matter integrity

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

Cited by 51 publications

References 44 publications

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

PACAP27 regulates ciliary function in primary cultures of rat brain ependymal cells

Ulk4 deficiency leads to hypomyelination in mice

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