CHICKEN OVALBUMIN UPSTREAM PROMOTER-TRANSCRIPTION FACTOR (COUP-TF) MODULATES EXPRESSION OF THE PURKINJE-CELL PROTEIN-2 GENE - A POTENTIAL ROLE FOR COUP-TF IN REPRESSING PREMATURE THYROID-HORMONE ACTION IN THE DEVELOPING BRAIN

The cerebellar Purkinje cell-specific PCP-2 gene is transcriptionally activated by thyroid hormone during the 2nd and 3rd weeks of postnatal life in the rat. In contrast, thyroid hormone has no detectable effec ts on PCP-2 expression in the fetal rat. We now present data that sugg est that the orphan nuclear receptor chicken ovalbumin upstream promot er-transcription factor (COUP-TF) represses triiodothyronine (T3)-depe ndent transcriptional activation of PCP-2 in the immature Purkinje cel l. Gel shift assays show that the PCP-2 A1TRE and adjoining sequences (-295/-199 region) bind to rat and mouse brain nucleoproteins in a dev elopmentally regulated fashion and that one of these nucleoproteins co uld be the orphan nucleoprotein COUP-TF. In support of this hypothesis , in vitro translated COUP-TF binds to the -295/-199 region and COUP-T F represses T3-dependent activation of the PCP-S promoter in transient transfection analyses. Finally, immunohistochemical studies reveal th at COUP-TF is specifically expressed in the immature fetal and early n eonatal Purkinje cell. and that this expression diminishes coincident with thyroid hormone induction of POP-a expression. Our findings are c onsistent with the hypothesis that the presence or absence of inhibito ry proteins bound to the thyroid hormone response element of T3-respon sive genes governs the responsivity of these genes to thyroid hormone during brain development.