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Molecular and Cellular Biology, April 2005, p. 2722-2732, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2722-2732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Deficits in Motor Coordination with Aberrant Cerebellar Development in Mice Lacking Testicular Orphan Nuclear Receptor 4{dagger}

Yei-Tsung Chen,1 Loretta L. Collins,1 Hideo Uno,2 and Chawnshang Chang1*

Departments of Pathology, Urology, and Radiation Oncology, George Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York,1 Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin2

Received 10 May 2004/ Returned for modification 12 June 2004/ Accepted 14 December 2004

Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological function has remained largely unknown. Throughout postnatal development, TR4-knockout (TR4–/–) mice exhibited behavioral deficits in motor coordination, suggesting impaired cerebellar function. Histological examination of the postnatal TR4–/– cerebellum revealed gross abnormalities in foliation; specifically, lobule VII in the anterior vermis was missing. Further analyses demonstrated that the laminations of the TR4–/– cerebellar cortex were changed, including reductions in the thickness of the molecular layer and the internal granule layer, as well as delayed disappearance of the external granule cell layer (EGL). These lamination irregularities may result from interference with granule cell proliferation within the EGL, delayed inward migration of postmitotic granule cells, and a higher incidence of apoptotis. In addition, abnormal development of Purkinje cells was observed in the postnatal TR4–/– cerebellum, as evidenced by aberrant dendritic arborization and reduced calbindin staining intensity. Expression of Pax-6, Sonic Hedgehog (Shh), astrotactin (Astn), reelin, and Cdk-5, genes correlated with the morphological development of the cerebellum, is reduced in the developing TR4–/– cerebellum. Together, our findings suggest that TR4 is required for normal cerebellar development.

* Corresponding author. Mailing address: University of Rochester Medical Center, Department of Pathology, Box 626, 601 Elmwood Ave., Rochester, NY 14642. Phone: (585) 273-4500. Fax: (585) 756-4133. E-mail:chang{at}urmc.rochester.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2005, p. 2722-2732, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2722-2732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Shyr, C.-R., Kang, H.-Y., Tsai, M.-Y., Liu, N.-C., Ku, P.-Y., Huang, K.-E., Chang, C. (2009). Roles of Testicular Orphan Nuclear Receptors 2 and 4 in Early Embryonic Development and Embryonic Stem Cells. Endocrinology 150: 2454-2462 [Abstract] [Full Text]  
  • Li, G., Lee, Y.-F., Liu, S., Cai, Y., Xie, S., Liu, N.-C., Bao, B.-Y., Chen, Z., Chang, C. (2008). Oxidative Stress Stimulates Testicular Orphan Receptor 4 through Forkhead Transcription Factor Forkhead Box O3a. Endocrinology 149: 3490-3499 [Abstract] [Full Text]  
  • Liu, N.-C., Lin, W.-J., Kim, E., Collins, L. L., Lin, H.-Y., Yu, I-C., Sparks, J. D., Chen, L.-M., Lee, Y.-F., Chang, C. (2007). Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase Mediated Gluconeogenesis. Diabetes 56: 2901-2909 [Abstract] [Full Text]  
  • Tanabe, O., Shen, Y., Liu, Q., Campbell, A. D., Kuroha, T., Yamamoto, M., Engel, J. D. (2007). The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription. Genes Dev. 21: 2832-2844 [Abstract] [Full Text]  
  • Zhang, Y., Chen, Y.-T., Xie, S., Wang, L., Lee, Y.-F., Chang, S.-S., Chang, C. (2007). Loss of Testicular Orphan Receptor 4 Impairs Normal Myelination in Mouse Forebrain. Mol. Endocrinol. 21: 908-920 [Abstract] [Full Text]  
  • Benoit, G., Cooney, A., Giguere, V., Ingraham, H., Lazar, M., Muscat, G., Perlmann, T., Renaud, J.-P., Schwabe, J., Sladek, F., Tsai, M.-J., Laudet, V. (2006). International Union of Pharmacology. LXVI. Orphan Nuclear Receptors. Pharmacol. Rev. 58: 798-836 [Abstract] [Full Text]  
  • Huq, M. D. M., Gupta, P., Tsai, N.-P., Wei, L.-N. (2006). Modulation of Testicular Receptor 4 Activity by Mitogen-activated Protein Kinase-mediated Phosphorylation. Mol. Cell. Proteomics 5: 2072-2082 [Abstract] [Full Text]  


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