Exp

Exp. feedback loop; furthermore, Nurr1 inhibition of -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 -catenin, providing a mechanism by which Nurr1 could be regulated by Wnt signaling. Expression and maintenance of the dopaminergic Tasosartan phenotype in the ventral midbrain (VM) require the orphan nuclear receptor (NR) Nurr1 (NR4A2) (48, 59). Genetic ablation of produces embryonic lethality due to a nearly complete absence specifically of mesencephalic dopaminergic neurons, which are critical for motor function. Nurr1 regulates both the differentiation and the maintenance of these dopaminergic cells, as = 135 RNAs]; 0.001) (unpublished observations). It will be interesting to determine if Nurr1+ neuronal precursors respond differentially to Wnt signaling compared to Nurr1? cells in vivo. In addition to the well-studied role for Wnt signaling during CNS development of the VM dopaminergic system, aberrant Wnt signaling has been implicated in several psychiatric and neurological disorders, such as bipolar disorder (19) and schizophrenia (16). Given the importance of CD226 the dopaminergic system in these diseases, it is conceivable that Wnt signaling could, in part, affect the activity of Nurr1. Interestingly, both LiCl and valproic acid, drugs useful in a number of mental disorders, inhibit GSK3, and recent data suggest that certain antipsychotics modulate this system as well (1, 2, 30). We show here that naturally occurring Nurr1 mutants have a reduced ability to inhibit -catenin transcription from a TCF/LEF element and appear to differentially regulate -catenin accumulation and KCNIP4 promoter activation. Future Tasosartan studies that determine if the functional interplay between -catenin and Nurr1 varies with disease state and is modulated by genetic factors will be of interest. Acknowledgments We thank T. Iwatsubo for the kind gift of KCNIP4 antibodies, Ung-il Chung Tasosartan for technical support with handling retrovirus, and J. Yanagisawa for critical reading of the manuscript. We also thank H. Higuchi and Y. Nagasawa for manuscript preparation. This work was partially supported by the 19th Research Fellowship from the Naito Memorial Foundation (2003) and by a research fellowship from the Uehara Memorial Foundation (2004). Footnotes ?Published ahead of print on 20 August 2007. REFERENCES 1. Alimohamad, H., N. Rajakumar, Y. H. Seah, and W. Rushlow. 2005. Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol. Psych. 57: 533-542. [PubMed] [Google Scholar] 2. Alimohamad, H., L. Sutton, J. Mouyal, N. Rajakumar, and W. J. Rushlow. 2005. The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. J. Neurochem. 95: 513-525. [PubMed] [Google Scholar] 3. Armogida, M., A. Petit, B. Vincent, S. Scarzello, C. A. da Costa, and F. Checler. 2001. Endogenous beta-amyloid production in presenilin-deficient embryonic mouse fibroblasts. Nat. Cell Biol 3: 1030-1033. [PubMed] [Google Scholar] 4. Cadigan, K. M., and Y. I. Liu. 2006. Wnt signaling: complexity at the surface. J. Cell Sci. 119: 395-402. [PubMed] [Google Scholar] 5. Castelo-Branco, G., and E. Arenas. 2006. Function of Wnts in dopaminergic neuron development. Neurodegener. Dis. 3: 5-11. [PubMed] [Google Scholar] 6. Castelo-Branco, G., K. M. Sousa, V. Bryja, L. Pinto, J. Wagner, and E. Arenas. 2006. Ventral midbrain glia express region-specific transcription factors and regulate dopaminergic neurogenesis through Wnt-5a secretion. Mol. Cell. Neurosci. 31: 251-262. [PubMed] [Google Scholar] 7. Castelo-Branco, G., J. Wagner, F. J. Rodriguez, J. Kele, K. Sousa, N. Rawal, H. A. Pasolli, E. Fuchs, J. Kitajewski, and E. Arenas. 2003. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc. Natl. Acad. Sci. USA 100: 12747-12752. [PMC free article] [PubMed] [Google Scholar] 8. Castro, D. S., M. Arvidsson, M. Bondesson Bolin, and T. Perlmann. 1999. Activity of the Nurr1 carboxyl-terminal domain depends on cell type and integrity of the activation function 2. J. Biol. Chem. 274: 37483-37490. [PubMed] [Google Scholar] 9. Chan, H. M., and N. B. La Thangue. 2001. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J. Cell Sci. 114: 2363-2373. [PubMed] [Google Scholar] 10. Chu, Y., K. Kompoliti, E. J. Cochran, E. J. Mufson, and J. H. Kordower. 2002. Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J. Comp. Neurol. 450: 203-214. [PubMed] [Google Scholar] 11..