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J. Biol. Chem., Vol. 276, Issue 46, 43277-43284, November 16, 2001
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From the Dopamine cells are generated in the ventral
midbrain during embryonic development. The progressive degeneration of
these cells in patients with Parkinson's disease, and the potential
therapeutic benefit by transplantation of in vitro
generated dopamine cells, has triggered intense interest in
understanding the process whereby these cells develop. Nurr1 is an
orphan nuclear receptor essential for the development of midbrain
dopaminergic neurons. However, the mechanism by which Nurr1 promotes
dopamine cell differentiation has remained unknown. In this study we
have used a dopamine-synthesizing cell line (MN9D) with immature
characteristics to analyze the function of Nurr1 in dopamine cell
development. The results demonstrate that Nurr1 can induce cell cycle
arrest and a highly differentiated cell morphology in these cells.
These two functions were both mediated through a DNA
binding-dependent mechanism that did not require Nurr1
interaction with the heterodimerization partner retinoid X receptor.
However, retinoids can promote the differentiation of MN9D cells
independently of Nurr1. Importantly, the closely related orphan
receptors NGFI-B and Nor1 were also able to induce cell cycle arrest
and differentiation. Thus, the growth inhibitory activities of the
NGFI-B/Nurr1/Nor1 orphan receptors, along with their widespread
expression patterns both during development and in the adult, suggest a
more general role in control of cell proliferation in the developing
embryo and in adult tissues.
Induction of Cell Cycle Arrest and Morphological
Differentiation by Nurr1 and Retinoids in Dopamine MN9D Cells*
§,¶
,,,,§§
Ludwig Institute for Cancer Research, Box
240, S-171 77 Stockholm, Sweden, the
Department of Cell and Molecular Biology,
Karolinska Institute, S-171 77 Stockholm, Sweden, and the
** Department of Neurobiology, Pharmacology, and Physiology,
the University of Chicago, Chicago, Illinois 60637
*
This work was supported in part by a grant from the
Göran Gustafsson Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to this work.
§§
To whom correspondence should be addressed. Tel.: 46 8 728 71 06;
Fax: 46 8 33 28 12; E-mail: Thomas.Perlmann@licr.ki.se.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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