Members of this class of so-called orphan receptors act as ligand-activated transcription factors. The
proteins have an N-terminal transactivation domain, a central DNA-binding domain with 2 zinc
fingers and a ligand-binding domain at the C terminus. Chang et al. (1994) cloned NR2C2, or TR4, a member of the nuclear hormone
receptor superfamily, using degenerate PCR on RNA from the supraoptic nucleus of the brain with
primers based on the conserved DNA-binding domain of these genes. They isolated TR4 cDNAs
from both human and rat libraries. The cDNAs encode a predicted 615-amino acid human protein and
a 596-amino acid rat protein that are 98% identical.
General function
Receptor, Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Comment
Expression regulated by
Comment
Ovarian localization
Comment
Yoshikawa et al. (1996) used RT-PCR to show that in rat and human, 2 isoforms (with and without a
19 codon exon) could be detected; in human, they were both expressed widely in tissues including
brain, placenta, and ovary.
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Subfertility with Defective Folliculogenesis in Female Mice Lacking TR4 Orphan Nuclear Receptor. Chen LM et al. Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found that female mice lacking TR4 (TR4(-/-)) displayed subfertility and irregular estrous cycles. TR4(-/-) female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4(-/-) female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4(-/-) ovaries. Functional analyses suggest that subfertility in TR4(-/-) female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary gonoadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce luteinizing hormone receptor (LHR) gene expression via direct binding to its 5' promoter. The consequence of reduced LHR expression in TR4(-/-) female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis.