Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor

University of Rochester, Rochester, New York, United States
Brain Research (Impact Factor: 2.84). 10/2007; 1168(1):72-82. DOI: 10.1016/j.brainres.2007.06.069
Source: PubMed


Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4(-/-)) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4(-/-) brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4(-/-) cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4(-/-) cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4(-/-) cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4(-/-) mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4(-/-) brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development.

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    • "Smaller litter size and difficulties with pup care have been described in Purkinje cell degeneration (pcd; Agtpbp1 pcd ) mice (Mullen et al. 1976). It has been assumed that affected motor coordination in cerebellar mutants influences sexual activity, nest-building behavior and pup rearing (Chen et al. 2007; Guastavino et al. 1993), but other authors have suggested that this behavioral deficiency could be caused by a global effect of the mutation on other systems (e.g. endocrine system) (Bulloch et al. 1982). "
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    • "The projection neurons of lamina I are either pain (nociceptive; red) and itch (pruritoceptive; dark blue) specific, or they receive convergent input from primary afferents that respond to both pain and itch-producing stimuli. Depending on the nature of the specificity within the TRPV1 afferent population (for example a GRPexpressing pruritoceptor population has been proposed [Sun and Chen, 2007]), there may be specificity of information flow from the primary afferents to the projection neurons (see text for details). The schematic also illustrates how primary afferent nociceptors (likely A delta afferents) can engage flexor reflex withdrawal circuitry (light blue interneurons) independently of their activation of interneuronal circuits in the superficial dorsal horn. "
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    ABSTRACT: The human testicular receptor 2 and 4 (TR2 and TR4) are two evolutionarily related orphan nuclear receptors belonging to the same nuclear receptor subfamily (Lee et al. 2002, J Steroid Biochem Mol Biol 81(4–5), 291–308). They regulate gene expression by binding to DNA as homodimers or a heterodimer with each other. TR4 may also cross-talk with other nuclear receptors, to control its target genes. In vitro and in vivo studies have identified several TR4 target genes, including ciliary neurotrophic factor alpha (CNTFRα) (Young et al. 1997, J Biol Chem 272(5), 3109–3116), apolipoprotein E (ApoE) (Kim et al. 2003, J Biol Chem 278(47), 46919–46926) and phosphenolpyruvate carboxykinase (PEPCK) (Liu et al. 2007, Diabetes 56(12), 2901–2909). Recent studies using TR4 knockout (TR4–/–) mice suggested that TR4 may play essential roles in growth, development, and metabolism (Zhang et al. 2007, Mol Endocrinol 21(4), 908–920; Kim et al. 2005, Biochem Biophys Res Commun 328(1), 85–90; Chen et al. 2005, Mol Cell Biol 25(7), 2722–2732; Mu et al. 2004, Mol Cell Biol 24(13), 5887–5899; Collins et al. 2004, Proc Natl Acad Sci U S A 101(42), 15058–15063). Mice with a germline deletion of TR4 are viable but have high early postnatal mortality, growth retardation, and profound reduction in body weight. Further studies showed that TR4 plays essential roles in the development and functioning in the central nervous system (Chen et al. 2005, Mol Cell Biol 25(7), 2722–2732), such as proper myelination and oligodendrocyte differentiation (Zhang et al. 2007, Mol Endocrinol 21(4), 908–920). Studies also showed that TR4 is important for spermatogenesis in male mice (Mu et al. 2004, Mol Cell Biol 24(13), 5887–5899) and folliculogenesis in female mice (Chen et al. 2008, Mol Endocrinol 22, 858–867). In addition, TR4 might be involved in skeletal muscle function and bone remodeling. TR4 and TR2 also regulate embryonic and fetal globin gene transcription (Tanabe et al. 2002, EMBO J 21(13), 3434–3442; Tanabe et al. 2007, EMBO J 26(9), 2295–2306). Surprisingly, mice lacking TR2 are viable and have no serious developmental defects. Thus, TR2 may either not be important in spermatogenesis and testis development, or its roles may be compensated by other closely related proteins such as TR4. Therefore, this chapter will focus on the in vivo roles of TR4.
    03/2010: pages 327-343;
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