Radial migration of pyramidal neurons is an important event during the development of cerebral cortex. Neurons experience series of morphological and directional transitions to get to their final laminar positions. Here we report that the histone methyltransferase enhancer of zest homolog 2 (Ezh2) is involved in the regulation of cortical radial migration. We show that Ezh2 knockdown leads to disturbed neuronal orientation, which results in the impairment of radial migration. Further results reveal that this migration deficiency may be due to the derepression of Reelin transcription in the migrating neurons. Our study provides evidence that epigenetic regulation of Reelin by Ezh2 maintains appropriate Reelin expression pattern to fulfill proper orientation of migrating neurons.

No abstract

Macrophage migration inhibitory factor (MIF) functions as a pleiotropic protein, participating in a vast array of cellular and biological processes. Abnormal expression of MIF has been implicated in many neurological diseases, including Parkinson's disease, epilepsy, Alzheimer's Disease, stroke, and neuropathic pain. However, the expression patterns of mif transcript and MIF protein from the early postnatal period through adulthood in the mouse brain are still poorly understood. We therefore investigated the temporal and spatial expression of MIF in the mouse neocortex during postnatal development in detail and partially in posterior piriform cortices (pPC). As determined by quantitative real-time PCR (qPCR), mif transcript gradually increased during development, with the highest level noted at postnatal day 30 (P30) followed by a sharp decline at P75. In contrast, Western blotting results showed that MIF increased constantly from P7 to P75. The highest level of MIF was at P75, while the lowest level of MIF was at P7. Immunofluorescence histochemistry revealed that MIF-immunoreactive (ir) cells were within the entire depth of the developed neocortex, and MIF was heterogeneously distributed among cortical cells, especially at P7, P14, P30, and P75; MIF was abundant in the pyramidal layer within pPC. Double immunostaining showed that all the mature neurons were MIF-ir and all the intensely stained MIF-ir cells were parvalbumin positive (Pv +) at adult. Moreover, it was demonstrated that MIF protein localized in the perikaryon, processes, presynaptic structures, and the nucleus in neurons. Taken together, the developmentally regulated expression and the subcellular localization of MIF should form a platform for an analysis of MIF neurodevelopmental biology and MIF-related nerve diseases.

No abstract

Activation of the Ras signaling pathway promotes the growth of malignant human glioblastoma multiforme (GBM). Mutations in Ras are rare in GBM, elevated levels of activated Ras are prevalently observed in GBM. However, the potential mechanism of how Ras is activated in GBM remains unclear.In this study, we screened a new interacted protein of Ras, PHLDA1. Our ndings con rmed that PHLDA1 acted as an oncogene and promoted GBM progression and recurrence. We demonstrated that PHLDA1 was upregulated in GBM tissues and cells. PHLDA1 overexpression promoted cell proliferation and tumor growth. In terms of mechanism, PHLDA1 promoted cell proliferation by regulating Ras/Raf/Mek/Erk signaling pathway. Moreover, Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation. PHLDA1 and Src competed binding with Ras, inhibiting Ras phosphorylation by Src and rescuing Ras activity. This study may provide a new idea of the molecular mechanism underlying glioblastoma progression and a novel potential therapeutic target for the comprehensive glioblastoma treatment.

The primary objective of this investigation was to assess the neuroprotective efficacy of lithium in an acrylamide (ACR)-induced neuropathy model in mice. In this study, Kunming male mice were administered ACR (25 mg/kg bw, i.p. once a day) with or without lithium (25 mg/kg bw, i.p. once a day) for 2 weeks. All ACR-administered mice exhibited severe symptoms of neuropathy. We found that treatment with lithium effectively alleviated behavioral deficits in animals elicited by acrylamide. Interestingly, the reduction of hippocampal neurogenesis resulting from ACR injection was promoted by administration of lithium. Further, lithium treatment significantly offset ACR-induced depletion in p-GSK-3β (Ser9) levels in hippocampus. Collectively our findings suggest the propensity of lithium to attenuate ACR-induced neuropathy. Further studies are necessary to understand the precise molecular mechanism by which the lithium attenuates neuropathy. Nevertheless, our data clearly demonstrate the beneficial effects of lithium on ACR-induced neuropathy in mice and suggest its possible therapeutic application as an adjuvant in the management of other forms of neuropathy in humans.

Radial spoke protein 3 (RSP3) was first identified in Chlamydomonas as a component of radial spoke, which is important for flagellar motility. The mammalian homolog of the Chlamydomonas RSP3 protein is found to be a mammalian protein kinase A-anchoring protein that binds ERK1/2. Here we show that mouse RSP3 is a nucleocytoplasmic shuttling protein. The full-length RSP3-EGFP fusion protein is mainly located in the cytoplasm of Chinese hamster ovary cells. However, by using deletion mutants of RSP3, we identified two nuclear localization signals and a nuclear export signal in RSP3. Moreover, using in utero electroporation, we found that overexpression of RSP3 in the developing cerebral cortex promotes neurogenesis. The layer II/III of the neocortex was much thicker in the RSP3-transfected region than that of the untransfected region in the neocortex. We also show that RSP3 is specifically located in the primary cilia of the radial glial cells, where it acts as a signaling mediator that regulates neurogenesis. Thus, our results suggest that RSP3 is a nucleocytoplasmic shuttling protein and plays an essential role in neurogenesis.

Occupational and environmental exposures to lead (Pb), one of the toxic metal pollutants, is of global concern. The present study aims to investigate the protective effects of lithium (Li) against Pb-induced damage in vivo and in vitro. For this purpose, 3-month-old mice received Li (250 mg per kg body weight, i.p.) and 2 hours later water containing Pb (20 mg per kg body weight, i.p.) for 2-weeks. Treatment of mice with Pb induced remarkable morphological damage in multiple organs, such as swelling and necrosis in the liver, kidney and spleen. Immunohistochemistry demonstrated that the number of newly generated cells and immature neurons in the hippocampus was significantly decreased in mice exposed to Pb when compared with those that received saline for control or Li. Furthermore, in mice exposed to Pb a higher percentage of newly generated cells differentiated into glial cells and fewer into neurons, and less newborn cells survived compared to those in controls and Li-treated mice. In mice exposed to Pb cognitive tests were impaired. Interestingly, pre-administration of Li markedly decreased Pb-induced pathological and neurological lesions in vivo and in vitro. Specifically, the reduction of hippocampal neurogenesis resulting from Pb exposure was prevented by administration of Li. In addition, we found that pretreatment with Li effectively prevented cognitive impairment in mice exposed to Pb. Furthermore, Li pretreatment significantly improved Pb-induced depletion in p-GSK-3β (Ser9) and microRNA-34c levels in the hippocampus. Collectively our findings point to the capacity of Li to attenuate Pb-induced damage.