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Initiation of Dopaminergic Differentiation of Nurr1^- Mesencephalic Precursor Cells Depends on Activation of Multiple Mitogen-Activated Protein Kinase Pathways

Sabolek, Michael and Baumann, Bernd and Heinrich, Maria and Meyer, Anne K. and Herborg, Anna and Liebau, Stefan and Maisel, Martina and Hermann, Andreas and Ventz, Katharina and Schwarz, Johannes and Wirth, Thomas and Storch, Alexander (2009) Initiation of Dopaminergic Differentiation of Nurr1^- Mesencephalic Precursor Cells Depends on Activation of Multiple Mitogen-Activated Protein Kinase Pathways. Stem Cells, 27 (8). pp. 2009-2021. ISSN 1549-4918. https://resolver.caltech.edu/CaltechAUTHORS:20091013-093446646

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Abstract

Interleukin-1 (IL-1) plays a pivotal role in terminal dopaminergic differentiation of midbrain-derived neural precursor cells already committed to the mesencephalic dopaminergic phenotype (named mdNPCs for mesencephalic dopaminergic neural precursor cells). Here we characterized the molecular events in long-term expanded rat nuclear receptor related-1^- (Nurr1^-) mdNPCs in response to IL-1β during their terminal dopaminergic specification. We showed that IL-1β induced a rapid induction of mRNA of dopaminergic key fate-determining transcription factors, such as Nurr1 and Pitx3, and a subsequent increase of tyrosine hydroxylase protein as an early marker for dopaminergic neurons in vitro. These effects of IL-1β were specific for mdNPCs and were not observed in striatal neural precursor cells (NPCs). Surprisingly, IL-1β did not activate the NF-κB pathway or the transcription factor activating protein 1 (AP-1), but inhibition of nuclear translocation of NF-κB by SN50 facilitated IL-1β-induced Nurr1 expression and dopaminergic differentiation of mdNPCs. Incubation of mdNPCs with IL-1β led to a rapid phosphorylation of ERK1/2 and p38 mitogen-activated protein (MAP) kinases within 1 to 3 hours, whereas Jun kinase was not phosphorylated in response to IL-1β. Consistently, inhibition of the ERK1/2 pathway or p38 MAP kinase blocked Nurr1 upregulation and further dopaminergic specification of mdNPCs, but not differentiation into MAP2ab^+ neurons. IL-1 receptor antagonist did not block early dopaminergic differentiation events, suggesting that the effects of IL-1β are not mediated through activation of IL-1 receptor type I. Our results indicate that induction of terminal dopaminergic specification of Nurr1^- mdNPCs by IL-1β depends on activation of the ERK1/2 and p38 MAP kinase pathway.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/stem.122DOIUNSPECIFIED
http://www3.interscience.wiley.com/journal/122385696/abstract?CRETRY=1&SRETRY=0PublisherUNSPECIFIED
Additional Information:Copyright © 2009 AlphaMed Press. Received: 20 October 2008; Accepted: 5 May 2009. First published online in STEM CELLS EXPRESS May 14, 2009. We thank Vera Lehmensiek and Hans-Jörg Habisch for fruitful discussions; Susanne Rubenwolf for her help with TH Western blotting; and Thomas Lenk, Nancy Meyer, Carmen Friebel, and Sylvia Kanzler for technical assistance. A.S. received financial support in part for this work from the IZKF Ulm to (project D6). J.S. and A.S. received financial support in part from the Bundesministerium für Bildung und Forschung (Förderprogramm Functional Proteome Analysis) (AZ 0312821 B). A.S. and A.H. received financial support in part from the Deutsche Forschungsgemeinschaft through the DFG-Research Center for Regenerative Therapies Dresden. M.S. was supported by a fellowship of the IZKF Ulm. B.B. was supported in part by the Deutsche Forschungsgemeinschaft (DFG KFO167/P5). A.H. was supported by an IZKF Ulm fellowship as a member of the Deutsche Forschungsgemeinschaft graduate college GRK460. A.K.M. is a member of the DFG graduate college GRK864. M.S. is currently affiliated with the Department of Neurology, University of Greifswald, Greifswald, Germany. Author contributions: M.S.: conception and design, provision of study material, collection and/or assembly of data, data analysis and interpretation, grant support, manuscript writing; B.B.: design, provision of study material, collection and/or assembly of data, data analysis and interpretation, manuscript writing; M.H.: collection and/or assembly of data; A.K.M.: collection and/or assembly of data, data analysis and interpretation; A. Herborg: Collection and/or assembly of data; S.L.: collection and/or assembly of data; M.M.: collection and/or assembly of data, provision of study material; A. Hermann: collection and/or assembly of data, provision of study material, manuscript writing; K.V.: chromosome analysis, manuscript writing; J.S.: data analysis and interpretation, manuscript writing; T.W.: provision of study material, data analysis and interpretation; A.S.: conception and design, principal investigator and grant support, provision of study material, collection and/or assembly of data, data analysis and interpretation, writing and finalizing the manuscript. See www.StemCells.com for supporting information available online.
Funders:
Funding AgencyGrant Number
IZKF UlmD6
Bundesministerium für Bildung und ForschungUNSPECIFIED
Deutsche ForschungsgemeinschaftDFG KFO167/P5
Subject Keywords:Mesencephalic precursor cells; Dopaminergic differentiation; Nuclear receptor related-1; Interleukin-1; Neural stem cells; NF-κB; Mitogen-activated protein kinase
Issue or Number:8
Record Number:CaltechAUTHORS:20091013-093446646
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20091013-093446646
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16289
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:22 Oct 2009 18:17
Last Modified:03 Oct 2019 01:09

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