This Article Full Text Full Text (PDF) Other Versions of this Article: MCB.00409-07v1 27/21/7486    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kitagawa, H. Articles by Freedman, L. P. Search for Related Content PubMed PubMed Citation Articles by Kitagawa, H. Articles by Freedman, L. P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2007, p. 7486-7496, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00409-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling

Hirochika Kitagawa ,^1,2, William J. Ray ,^1,, Helmut Glantschnig,¹ Pascale V. Nantermet,¹ Yuanjiang Yu,^1, Chih-Tai Leu,¹ Shun-ichi Harada,¹ Shigeaki Kato,^2,3 and Leonard P. Freedman^1*

Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania 19486,¹ Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan,² ERATO, Japan Science and Technology Agency, Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan³

Received 8 March 2007/ Returned for modification 10 April 2007/ Accepted 3 August 2007

The orphan nuclear receptor Nurr1 is essential for the development and maintenance of midbrain dopaminergic neurons, the cells that degenerate during Parkinson's disease, by promoting the transcription of genes involved in dopaminergic neurotransmission. Since Nurr1 lacks a classical ligand-binding pocket, it is not clear which factors regulate its activity and how these factors are affected during disease pathogenesis. Since Wnt signaling via ß-catenin promotes the differentiation of Nurr1⁺ dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that ß-catenin and Nurr1 functionally interact at multiple levels. In the absence of ß-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. ß-Catenin binds Nurr1 and disrupts these corepressor complexes, leading to coactivator recruitment and induction of Wnt- and Nurr1-responsive genes. We then identified KCNIP4/calsenilin-like protein as being responsive to concurrent activation by Nurr1 and ß-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote ß-catenin degradation, we tested the possibility that KCNIP4 induction regulates ß-catenin signaling. KCNIP4 induction limited ß-catenin activity in a presenilin-dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of ß-catenin activity was absent in PS1^–/– cells or in the presence of small interfering RNAs specific to KCNIP4. These data describe regulatory convergence between Nurr1 and ß-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.

Published ahead of print on 20 August 2007.

H.K. and W.J.R. gave equal contributions to this study.

Present address: Department of Alzheimer's Research, Merck Research Laboratories, West Point, PA 19486.