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 effects on PCP-2 expression in the fetal rat. We now present data that suggest that the orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) represses triiodothyronine (T3)-dependent transcriptional activation of PCP-2 in the immature Purkinje cell. Gel shift assays show that the PCP-2 A1TRE and adjoining sequences (-295/-199 region) bind to rat and mouse brain nucleoproteins in a developmentally regulated fashion and that one of these nucleoproteins could be the orphan nucleoprotein COUP-TF. In support of this hypothesis, in vitro translated COUP-TF binds to the -295/-199 region and COUP-TF represses T3-dependent activation of the PCP-2 promoter in transient transfection analyses. Finally, immunohistochemical studies reveal that COUP-TF is specifically expressed in the immature fetal and early neonatal Purkinje cell and that this expression diminishes coincident with thyroid hormone induction of PCP-2 expression. Our findings are consistent with the hypothesis that the presence or absence of inhibitory proteins bound to the thyroid hormone response element of T3-responsive genes governs the responsivity of these genes to thyroid hormone during brain development.
Anderson
G W
GW
Thyroid Research Unit, Division of Endocrinology and Diabetes, Department of Medicine, Cell Biology and Neuroanatomy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Larson
R J
RJ
Oas
D R
DR
Sandhofer
C R
CR
Schwartz
H L
HL
Mariash
C N
CN
Oppenheimer
J H
JH
D000818:Animals; D051838:COUP Transcription Factor I; D002531:Cerebellum / Q000166:cytology / Q000196:embryology*; D002645:Chickens; D004268:DNA-Binding Proteins / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics*; D009698:Nucleoproteins / Q000502:physiology; D010047:Ovalbumin; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011689:Purkinje Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014284:Triiodothyronine / Q000502:physiology*
D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009479:Neuropeptides; C497590:Nr2f1 protein, mouse; C497591:Nr2f1 protein, rat; D009698:Nucleoproteins; C104971:Pcp2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014284:Triiodothyronine; D010047:Ovalbumin