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Blocked MAP kinase activity selectively enhances neurotrophic growth responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
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2004 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 25, no 2, 345-354 p.Article in journal (Refereed) Published
Abstract [en]

Bone morphogenetic proteins (BMPs) 4 and 6 as well as MEK inhibitors PD98059 and U0126 potentiate neurotrophin 3 (NT3)- and neurturin (NTN)-induced neurite outgrowth and survival of peripheral neurons from the E9 chicken embryo. Preexposure to BMP4 or PD98059 was sufficient to prime the potentiation of subsequently added NT3. Phosphorylation of Erk2, induced by NT3, was reduced by MEK inhibition but unaffected by BMP signaling. Real-time PCR showed that neither BMP stimulation nor MEK inhibition increased Trk receptor expression and that the BMP-induced genes Smad6 and Id1 were not upregulated by PD98059. In contrast, both MEK inhibition and BMP signaling suppressed transcription of the serum-response element (SRE)-driven Egr1 gene. A reporter assay using NGF-stimulated PC12 cells demonstrated that MEK/Erk/Elk-driven transcriptional activity was inhibited by Smad1/5 and by PD98059. Thus, suppression of SRE-controlled transcription represents a likely convergence point for pathways regulating neurotrophic responses.

Place, publisher, year, edition, pages
2004. Vol. 25, no 2, 345-354 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-90337DOI: 10.1016/j.mcn.2003.10.015PubMedID: 15019950OAI: oai:DiVA.org:uu-90337DiVA: diva2:162654
Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2013-05-23Bibliographically approved
In thesis
1. Experimental Studies of BMP Signalling in Neuronal Cells
Open this publication in new window or tab >>Experimental Studies of BMP Signalling in Neuronal Cells
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.

This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 75 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1259
Neurosciences, Bone Morphogenetic Protein (BMP), Growth Differentiation Factor 10 (GDF10), Aktivne-receptor Like Kinase 2 (ALK2), Tyrosine Hydroxylase (TH), Neurotrophic Factor, Neurite Outgrowth, Hippocampus, Catecholamine, PC12, Sympathetic Ganglia, Substantia Nigra (SN), Gene Targeting, Neurovetenskap
National Category
Research subject
Developmental Neurosciences
urn:nbn:se:uu:diva-3398 (URN)91-554-5624-3 (ISBN)
Public defence
2003-05-16, B21, BMC, Uppsala, 09:15
Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2013-03-22Bibliographically approved

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