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Genetically modified bone morphogenetic protein signalling alters traumatic brain injury-induced gene expression responses in the adult mouse
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. Neurosci.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Neurokirurgi.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. neurosci.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. Neurosci.
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2006 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 84, no 1, 47-57 p.Article in journal (Refereed) Published
Abstract [en]

Three genetic mouse models were examined to define effects of bone morphogenetic protein (BMP) signalling on gene expression in normal and injured adult brain. CaMKII-Cre eliminated the BMP receptor Acvr1 (Alk2) and the common TGF beta superfamily signal mediator Smad4 or activated a constitutively active Acvr1 in postnatal forebrain neurons. All mutants followed mendelian ratios, with no overt phenotypic changes. In situ hybridization demonstrated normal patterns of the dendritic marker MAP2 (Mtap2) throughout cortex despite neuron-specific losses of Acvr1 or Smad4. However, strong up-regulation of Mtap2 transcript in these mice was found by quantitative RT-PCR (qRT-PCR), indicating that Mtap2 is normally suppressed by BMR Traumatic brain injury (TBI) resulted in increases of histone-associated DNA fragments in both control and Smad4-deficient cortex. Several cell-type-specific transcripts known to be involved in injury-related responses were measured by qRT-PCR. Gfap mRNA was strongly upregulated in controls as well as in the loss-of-BMP-signalling mutants. Notably, activated Acvr1 signalling gave significantly lower TBI-induced up-regulations of Gfap and Phox2a mRNA levels, indicating reductions in astroglial and neuronal reactions to injury. Strong impairment in injury-induced Timp1 transcript up-regulation was also seen in these mice. In contrast, osteopontin (Spp1) transcript levels in activated microglia were not reduced by Acvr1 signalling. Altogether, the data suggest that BMP signalling is dispensable in adult cortical neurons but that augmented BMP signalling affects molecular changes associated with neuronal lesions.

Place, publisher, year, edition, pages
2006. Vol. 84, no 1, 47-57 p.
Keyword [en]
TBI, activin receptor-1, Smad4, CaMKII-Cre, glial fibrillary acidic protein
National Category
URN: urn:nbn:se:uu:diva-82045DOI: 10.1002/jnr.20856ISI: 000238897400005PubMedID: 16583403OAI: oai:DiVA.org:uu-82045DiVA: diva2:109960
Available from: 2006-09-12 Created: 2006-09-12 Last updated: 2016-08-24Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 163
Neurosciences, traumatic brain injury, transcripts, GeneChip, chemokine, inflammation, mouse brain, neuroprotection, neuronal injury, neuroregeneration, astrocytosis, Neurovetenskap
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)
Available from: 2006-09-01 Created: 2006-09-01 Last updated: 2009-10-14Bibliographically approved

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Lewén, AndersHillered, LarsEbendal, Ted
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