The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development.

Since Testicular Receptor 4 (TR4) was cloned, efforts have been made to elucidate its physiological function. To examine the putative functions of TR4, the conventional TR4 knockout (TR4(-/-)) mouse model was generated. Throughout postnatal and adult stages, TR4(-/-) mice exhibited behavioral deficits in motor coordination, suggesting impaired cerebellar function. Histological examination of the postnatal and adult TR4(-/-) cerebellum revealed gross abnormalities in foliation. Further analyses demonstrated changes in the lamination of the TR4(-/-) cerebellar cortex, including reduction in the thickness of both the molecular layer (ML) and the internal granule layer (IGL). Analyses of the developing TR4(-/-) cerebellum indicate that the lamination irregularities observed may result from disrupted granule cell proliferation within the external granule cell layer (EGL), delayed inward migration of post-mitotic granule cells, and increased apoptosis during cerebellar development. In addition, abnormal development of Purkinje cells was observed in the postnatal TR4(-/-) cerebellum, as indicated by aberrant dendritic arborization. In postnatal, neuronal-specific TR4 knockout mice, architectural changes in the cerebellum were similar to those seen in TR4(-/-) animals, suggesting that TR4 function in neuronal lineages might be important for cerebellar morphogenesis, and that the effect on Purkinje cell development is likely mediated by changes elsewhere, such as in granule cells, or is highly dependent on developmental stage. Together, our findings from various TR4 knockout mouse models suggest that TR4 is required for normal cerebellar development and that failure to establish proper cytoarchitecture results in dysfunction of the cerebellum and leads to abnormal behavior.