Autoinduction of nuclear receptor genes and its significance

Although downregulation of receptors by their respective hormonal ligands is a well-studied phenomenon, relatively less is known about autoupregulation of receptors. However, an increasing number of observations of the latter process are now being reported. Here, we discuss the phenomenon of autoinduction of nuclear receptors of the steroid/thyroid hormone gene family, and its significance in the context of the developmental and gene regulatory function of the ligands. Much of this review is illustrated by recent work from our laboratory on the autoregulation of Xenopus estrogen (ER) and thyroid hormone (TR) receptors and their transcripts, accompanying or anticipating vitellogenesis and metamorphosis, respectively. The activation by estrogen (E2) of the silent vitellogenin genes and the induction of FOSP-1 genes in primary cultures of hepatocytes from male Xenopus and oviduct cells, respectively, are tightly coupled to a substantial upregulation of ER protein and its transcript. The developmental competence to activate vitellogenin in response to E2 was found to be acquired during late metamorphosis. Since the latter process is obligatorily controlled by thyroid hormones (TH), we extended our studies to the developmental and hormonal regulation of Xenopus TR genes. Although very low levels of TR alpha and beta mRNAs are detectable in embryos and early larvae, there is a large increase in the accumulation of both transcripts before the onset of metamorphosis (stage 54 tadpoles), by which time the larval thyroid gland has first begun to secrete TH. Filter and in situ hybridization revealed that the two transcripts were differentially regulated and were not equally distributed in all regions or tissues of the tadpole. Their concentration peaks at metamorphic climax and drops to low levels in froglets and adult Xenopus. Exogenous TH given to pre-metamorphic tadpoles is known to induce metamorphosis precociously. Administration of triiodothyronine (T3) to early tadpoles (stages 50/52) caused a rapid upregulation of TR alpha and beta mRNAs which was particularly marked for the beta transcript (20- to 50-fold increase in steady-state levels). This autoinduction, which is the earliest response to T3, is mimicked to variable degrees in some Xenopus cell lines. In XTC-2 cells, in which the in vivo process is fully reproduced, it was possible to show with cycloheximide that the increase in TR mRNA requires protein synthesis. It was also possible to show by transfection of XTC-2 cells with a reporter-promoter construct of Xenopus albumin gene, which is a target for T3, that the extra TR mRNA increases functional receptor in the cell. Although the role of TH is well-known in metamorphosis, we found that TR is also autoinduced in primary culture of adult male Xenopus hepatocytes. The significance of this finding lies in the fact that T3 potentiates the autoinduction of ER and the de novo activation of vitellogenin genes by E2. Prolactin (PRL) is known to exert a "juvenilizing" action by preventing the induction of amphibian metamorphosis by TH. It is therefore highly significant that PRL prevented both the autoinduction of TR alpha and beta mRNAs in whole tadpoles and organ cultures and the activation of TR target genes, such as those encoding albumin and 63 kDa adult-type keratin. Although how PRL exerts its antimetamorphic effect is not known, these findings lead us to propose a dual threshold model for the autoinduction of TR, whereby the autoinduction of TR genes requires a very low level of TR and TH to rapidly augment the amount of functional TR. This higher amount of receptor would be required to achieve a higher threshold to activate "downstream" or target genes which specify the adult phenotype at the end of metamorphosis. Finally, a survey of recent literature shows that the phenomenon of autoinduction is not restricted to Xenopus ER and TR but is more widespread among members of the nuclear receptor family.