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First published online April 17, 2008
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2007-0805v1
26/7/1683    most recent
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Submitted on September 21, 2007
Accepted on April 6, 2008

TISSUE-SPECIFIC STEM CELLS

TGF-{beta} Co-Operates with Persephin for Dopaminergic Phenotype Induction

Eleni Roussa 1*, Oliver Oehlke 2, Belal Rahhal 3, Stephan Heermann 3, Stefanie Heidrich 4, Michael Wiehle 4, Kerstin Krieglstein 2

1 Dept. for Neuroanatomy, Georg-August-University Goettingen, D-37075 Goettingen, Germany, DFG Research Center for the Molecular Physiology of the Brain (CMPB), Anatomy and Cell Biology II, Department of Molecular Embryology, Albert-Ludwigs-University Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany.
2 Anatomy and Cell Biology II, Department of Molecular Embryology, Albert-Ludwigs-University Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany.
3 Dept. for Neuroanatomy, Georg-August-University Goettingen, D-37075 Goettingen, Germany, DFG Research Center for the Molecular Physiology of the Brain (CMPB), Albert-Ludwigs-University Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany.
4 Dept. for Neuroanatomy, Georg-August-University Goettingen, D-37075 Goettingen, Germany

* To whom correspondence should be addressed. E-mail: eroussa{at}gwdg.de.


  Abstract

The aim of the present study was to investigate putative co-operative effects of transforming growth factor {beta} (TGF-{beta}) and glial cell-line derived neurotrophic factor (GDNF) family ligands (GFLs) in the differentiation of midbrain progenitors towards a dopaminergic phenotype. Therefore, a mouse midbrain E12 neurospheres culture has been used as an experimental model. We show that neurturin and persephin (PSPN), but not GDNF, are capable of transient induction of dopaminergic neurons in vitro. This process however, requires presence of endogenous TGF-{beta}. In contrast, after 8 days in vitro GDNF rescued the TGF-{beta}-neutralization-dependent loss of the TH positive cells. In vivo, at E14.5, no apparent phenotype concerning dopaminergic neurons was observed in tgf{beta}2-/-/gdnf-/- double mutant mice. In vitro, combined TGF-{beta}/PSPN treatment achieved a yield of approximately 20% of TH positive cells that were less vulnerable against MPP+ toxicity. The underlying TGF-{beta}/PSPN differentiation signaling is receptor-mediated, involving p38-MAPK and PI-3K pathways.

These results indicate that phenotype induction and survival of fully differentiated neurons are accomplished through distinct pathways and individual factor requirement. TGF-{beta} is required for the induction of dopaminergic neurons, whereas GDNF is required for regulating and/or maintaining a differentiated neuronal phenotype. Moreover, this study proposes combination of TGF-{beta} with PSPN as potent inductive factors for the generation of dopaminergic neurons that should be considered in tissue engineering and cell replacement therapies for Parkinson's disease.

______________________________________________________________________________

Author contributions: E.R.: Conception and design, Financial support, Collection and assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; O.O.: Collection and assembly of data, Data analysis and interpretation; B.R.: Collection and assembly of data; S.H.: Collection and assembly of data; S.H.: Collection and assembly of data; M.W.: Collection and assembly of data, Data analysis and interpretation; K.K.: Conception and design, Financial support, Data analysis and interpretation, Manuscript writing, Final approval of manuscript.

 Key Words. neurotrophins, cell fate, stem cells, transforming growth factor beta, neuronal differentiation






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