Previously, we reported that the nuclear orphan receptor TR4 could induce transcriptional activity via the 5th intron of the ciliary neurotrophic factor (CNTF) alpha receptor gene (CNTFR-I5). Here we show CNTF could increase TR4 expression and enhance the DNA-binding capacity of TR4. Interestingly, the expression of TR2, a close family member of TR4, could also be induced by CNTF. In return, TR2 induced CNTFRalpha transcriptional activity through binding to a direct repeat response element of AGGTCA within CNTFR-I5. The possibility of this mutual influence between TR2 and the CNTF signaling was further strengthened by in situ hybridization. Similar expression patterns of TR2 and CNTFRalpha were observed in most of the developing neural structures such as the ganglia, neural epithelia, spinal cord, and the periventricular areas of brain. Together, our data suggest that an interaction between TR2/TR4 and the CNTF signaling pathway may occur, supporting the hypothesis that TR2/TR4 may play important roles in neurogenesis.