AUTOINDUCTION OF NUCLEAR RECEPTOR GENES AND ITS SIGNIFICANCE

Although downregulation of receptors by their respective hormonal liga nds is a well-studied phenomenon, relatively less is known about autou pregulation of receptors. However, an increasing number of observation s of the latter process are now being reported. Here, we discuss the p henomenon of autoinduction of nuclear receptors of the steroid/thyroid hormone gene family, and its significance in the context of the devel opmental and gene regulatory function of the ligands. Much of this rev iew is illustrated by recent work from our laboratory on the autoregul ation of Xenopus estrogen (ER) and thyroid hormone (TR) receptors and their transcripts, accompanying or anticipating vitellogenesis and met amorphosis, respectively. The activation by estrogen (E2) of the silen t vitellogenin genes and the induction of FOSP-1 genes in primary cult ures of hepatocytes from male Xenopus and oviduct cells, respectively, are tightly coupled to a substantial upregulation of ER protein and i ts transcript. The developmental competence to activate vitellogenin i n response to E2 was found to be acquired during late metamorphosis. S ince the latter process is obligatorily controlled by thyroid hormones (TH), we extended our studies to the developmental and hormonal regul ation of Xenopus TR genes. Although very low levels of TRalpha and bet a mRNAs are detectable in embryos and early larvae, there is a large i ncrease in the accumulation of both transcripts before the onset of me tamorphosis (stage 54 tadpoles), by which time the larval thyroid glan d has first begun to secrete TH. Filter and in situ hybridization reve aled that the two transcripts were differentially regulated and were n ot 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 tadp oles is known to induce metamorphosis precociously. Administration of triiodothyronine (T3) to early tadpoles (stages 50/52) caused a rapid upregulation of TRalpha and beta mRNAs which was particularly marked f or the beta transcript (20- to 50-fold increase in steady-state levels ). This autoinduction, which is the earliest response to T3, is mimick ed 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 synt hesis. It was also possible to show by transfection of XTC-2 cells wit h a reporter-promoter construct of Xenopus albumin gene, which is a ta rget for T3, that the extra TR mRNA increases functional receptor in t he cell. Although the role of TH is well-known in metamorphosis, we fo und that TR is also autoinduced in primary culture of adult male Xenop us 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 ''juveni lizing'' action by preventing the induction of amphibian metamorphosis by TH. It is therefore highly significant that PRL prevented both the autoinduction of TRalpha and beta mRNAs in whole tadpoles and organ c ultures and the activation of TR target genes, such as those encoding albumin and 63 kDa adult-type keratin. Although how PRL exerts its ant imetamorphic effect is not known, these findings lead us to propose a dual threshold model for the autoinduction of TR, whereby the autoindu ction of TR genes requires a very low level of TR and TH to rapidly au gment the amount of functional TR. This higher amount of receptor woul d be required to achieve a higher threshold to activate ''downstream'' or target genes which specify the adult phenotype at the end of metam orphosis. Finally, a survey of recent literature shows that the phenom enon of autoinduction is not restricted to Xenopus ER and TR but is mo re widespread among members of the nuclear receptor family. Examples a re the upregulation of ecdysone receptor in Drosophila, and ER and rec eptors for retinoic acid and androgen in mammalian cells. It is conclu ded that such autoregulation may be a requirement for the growth and d evelopmental functions of the ligands of the nuclear receptor superfam ily.