A regulatory circuit mediating convergence between Nurr1 transcriptional regulation and Wnt signaling.
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 beta-catenin promotes the differentiation of Nurr1(+) dopaminergic precursors in vitro, we tested for functional interactions between these systems. We found that beta-catenin and Nurr1 functionally interact at multiple levels. In the absence of beta-catenin, Nurr1 is associated with Lef-1 in corepressor complexes. Beta-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 beta-catenin. Since KCNIP4 interacts with presenilins, the Alzheimer's disease-associated proteins that promote beta-catenin degradation, we tested the possibility that KCNIP4 induction regulates beta-catenin signaling. KCNIP4 induction limited beta-catenin activity in a presenilin-dependent manner, thereby serving as a negative feedback loop; furthermore, Nurr1 inhibition of beta-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 beta-catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling.
Kitagawa
Hirochika
H
Department of Molecular Endocrinology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Ray
William J
WJ
Glantschnig
Helmut
H
Nantermet
Pascale V
PV
Yu
Yuanjiang
Y
Leu
Chih-Tai
CT
Harada
Shun-ichi
S
Kato
Shigeaki
S
Freedman
Leonard P
LP
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D053764:Presenilin-1 / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D004268:DNA-Binding Proteins; C496753:KCNIP4 protein, human; D051605:Kv Channel-Interacting Proteins; C497575:Lef1 protein, rat; D051821:Lymphoid Enhancer-Binding Factor 1; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D053764:Presenilin-1; D012097:Repressor Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin
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