Dataset Information

Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.

ABSTRACT: Platelet-derived growth factor CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase 3beta (GSK3beta) activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal death, neurotoxin-induced neuronal injury, 6-hydroxydopamine-induced Parkinson's dopaminergic neuronal death, and ischemia-induced stroke, PDGF-CC protein or gene delivery protected different types of neurons from apoptosis in both the retina and brain. On the other hand, loss-of-function assays using PDGF-C null mice, neutralizing antibody, or short hairpin RNA showed that PDGF-CC deficiency/inhibition exacerbated neuronal death in different neuronal tissues in vivo. Mechanistically, we revealed that the neuroprotective effect of PDGF-CC was achieved by regulating GSK3beta phosphorylation and expression. Our data demonstrate that PDGF-CC is critically required for neuronal survival and may potentially be used to treat neurodegenerative diseases. Inhibition of the PDGF-CC-PDGF receptor pathway for different clinical purposes should be conducted with caution to preserve normal neuronal functions.

SUBMITTER: Tang Z

PROVIDER: S-EPMC2856029 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.

Tang Zhongshu Z Arjunan Pachiappan P Lee Chunsik C Li Yang Y Kumar Anil A Hou Xu X Wang Bin B Wardega Piotr P Zhang Fan F Dong Lijin L Zhang Yongqing Y Zhang Shi-Zhuang SZ Ding Hao H Fariss Robert N RN Becker Kevin G KG Lennartsson Johan J Nagai Nobuo N Cao Yihai Y Li Xuri X

The Journal of experimental medicine 20100315 4

Platelet-derived growth factor CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase 3beta (GSK3beta) activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal de ...[more]

PMID: 20231377

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Project description:Platelet-derived growth factor-CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report here a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase (GSK)3beta activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal death, neurotoxin-induced neuronal injury, 6-OHDA-induced Parkinson's dopaminergic neuronal death and ischemia-induced stroke, PDGF-CC protein or gene delivery protected different types of neurons from apoptosis in both the retina and brain. On the other hand, loss-of-function assays using PDGF-C null mice, neutralizing antibody or shRNA showed that PDGF-CC deficiency/inhibition exacerbated neuronal death in different neuronal tissues in vivo. Mechanistically, we revealed that the neuroprotective effect of PDGF-CC was achieved by regulating GSK3beta phosphorylation and expression. Our data demonstrate that PDGF-CC is critically required for neuronal survival, and may potentially be used to treat neurodegenerative diseases. Inhibition of the PDGF-CC/receptor pathway for different clinical purposes should be conducted with caution to preserve normal neuronal functions. PDGF-C deficient mice were bred onto C57BL/6 background for more than six generations and littermates were used. After optic nerve crush (ONC), PDGF-CC protein Ã 1 Âµl of active recombinant human PDGF-CC protein 0.5 Âµg/Âµl (rhPDGF-CC) was injected into mouse vitreous once a week for two weeks. Seven days after the ONC injury and PDGF-CC protein treatment, retinae were harvested and total RNA isolated using the TRIzol reagent (Invitrogen) followed by the RNeasy Mini kit (Qiagen) purification according to the manufacturer's instructions. Microarray assay was performed using the Mouse-6 Expression BeadChips containing approximately 24,000 annotated mouse transcripts (Illumina Inc). Three biological repeats were included in the microarray assay. Two tailed Student's t-test was used for statistical analysis of gene expression data. Functional grouping of the differentially expressed genes was performed using several different tools including the WebGestalt (http://bioinfo.vanderbilt.edu/webgestalt) and the Ingenuity Pathways Analysis (https://analysis.ingenuity.com/pa/login/login.jsp). The supplementary file 'GSE19207_non-normalized.txt' contains raw data for Samples GSM476021-GSM476026.

Project description:Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood-brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1-/-) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1-/- mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b+ cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1-/- mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability.

Dataset Information

Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.

Publications

Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.

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