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BMP enhances transcriptional responses to NGF during PC12 cell differentiation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Med utvecklingsbiologi. (Ebendal)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Med utvecklingsbiologi. (Ebendal)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Med utvecklingsbiologi. (Ebendal)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Med utvecklingsbiologi. (Ebendal)
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2005 (English)In: Neurochemical Research, ISSN 0364-3190, Vol. 30, no 6-7, 753-65 p.Article in journal (Other academic) Published
Abstract [en]

Bone morphogenetic proteins (BMPs) enhance neurite outgrowth in nerve growth factor (NGF)-stimulated PC12 cells. To investigate the mechanism of this potentiating effect, real-time PCR was used to analyze the expression of 45 selected genes. A robust increase in expression of 10 immediate early genes including Egr1-4, Hes1, Junb, Jun and Fos was observed already after 1 h treatment with NGF alone. NGF plus BMP4 further increased these transcripts at 1 h and activated 18 additional genes. BMP4 alone induced Smad6, Mtap1b and Hes1. Egr3 was the gene most strongly upregulated by NGF and BMP4. However, luciferase assays showed that the cloned Egr3 proximal promoter was not involved in the BMP4 potentiation. Blocking Egr3 and Junb function by dominant-negative constructs reduced neurite outgrowth under stimulating conditions, proving that activation of members of both the Egr and Jun families is necessary for maximal PC12 cell response to NGF and BMP4.

Place, publisher, year, edition, pages
2005. Vol. 30, no 6-7, 753-65 p.
Keyword [en]
Animals, Base Sequence, Bone Morphogenetic Proteins/*physiology, Cell Differentiation/*drug effects, Cluster Analysis, DNA Primers, Early Growth Response Protein 3/genetics, Gene Expression Regulation/genetics/physiology, Nerve Growth Factor/*pharmacology, PC12 Cells, Polymerase Chain Reaction, Promoter Regions (Genetics), Rats, Research Support; Non-U.S. Gov't, Transcription; Genetic/drug effects/*physiology
Identifiers
URN: urn:nbn:se:uu:diva-75413DOI: 10.1007/s11064-005-6868-6PubMedID: 16187211OAI: oai:DiVA.org:uu-75413DiVA: diva2:103323
Available from: 2006-02-07 Created: 2006-02-07 Last updated: 2009-10-12Bibliographically approved
In thesis
1. Molecular Characterization of Experimental Traumatic Brain Injury
Open this publication in new window or tab >>Molecular Characterization of Experimental Traumatic Brain Injury
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is the most common cause of mortality and disability in the younger (<50 years) Swedish population with an incidence rate of 20,000 cases per year. This thesis aims to increase the understanding of brain injury mechanisms, especially in a molecular and cellular context. Bone morphogenetic protein (BMP) signalling was examined in three genetically modified mice (two “loss-of-function”, one “gain-of-function”) exposed to TBI (controlled cortical impact, CCI) with CaMKII used as promoter for Cre-driven recombination in postnatal forebrain neurons. The mice survived, developed normally and did not show any obvious phenotypes except for an upregulation in Mtap2 mRNA in mice with impaired BMP signalling. Reactive Gfap and Timp1 mRNA expression measured using quantitative RT-PCR (qRT-PCR) was reduced in the mice overexpressing BMP signals. The BMP signalling pathway was further studied in cultured PC12 cells with BMP4 and NGF added. Egr3 expression was substantially increased by these growth factors. Blocking Egr or Junb functions reduced neurite outgrowth. TBI-induced mRNA expression changes in 100 selected genes in C57BL/6J mouse neocortex and hippocampus were measured using qRT-PCR at different time points post-injury. Several distinct gene clusters with similar expression patterns were identified. GeneChip analysis (Affymetrix) of the injured mouse neocortex at three days revealed 146 transcripts significantly upregulated, confirming and extending the qRT-PCR results. The findings demonstrate marked increases after injury among chemokine transcripts and activation of many genes involved in inflammation. In conclusion, the present study has revealed transcriptional changes in specific signalling pathways after brain injury. The results may help to identify novel targets for neuroprotective interventions after traumatic brain injury.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 163
Keyword
Neurosciences, traumatic brain injury, transcripts, GeneChip, chemokine, inflammation, mouse brain, neuroprotection, neuronal injury, neuroregeneration, astrocytosis, Neurovetenskap
Identifiers
urn:nbn:se:uu:diva-7087 (URN)91-554-6621-4 (ISBN)
Public defence
2006-09-22, B41, Biomedicinska centrum, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2006-09-01 Created: 2006-09-01 Last updated: 2009-10-14Bibliographically approved

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