Repression of gonadotropin-releasing hormone promoter activity by the POU homeodomain transcription factor SCIP/Oct-6/Tst-1: a regulatory mechanism of phenotype expression?
POU domain transcription factors are required for neuropeptide expression in selected subsets of hypothalamic neuroendocrine neurons. We now report that expression of the gonadotropin-releasing hormone (GnRH) gene, which controls sexual development, is regulated by the POU protein SCIP/Oct-6/Tst-1. Reverse transcriptase PCR cloning and RNase protection assays demonstrated the presence of SCIP/Oct-6/Tst-1 mRNA in the GnRH-producing neuronal cell line GT1-7. The physiological relevance of this regulatory activity was suggested by the detection of SCIP/Oct-6/Tst-1 mRNA in a subset of GnRH neurons in the hypothalamus of prepubertal female rats. Coexpression of SCIP/Oct-6/Tst-1 in neuronal cells inhibited rat GnRH (rGnRH) promoter activity via three regions of the proximal rGnRH promoter containing SCIP/Oct-6/Tst-1 binding sites. DNase I footprinting, gel shift assays, and DNA and protein mutagenesis studies indicated that both direct DNA binding and protein-protein interactions are required for SCIP/Oct-6/Tst-1 modulation of GnRH gene expression. Activation of SCIP/Oct-6/Tst-1 expression in terminally differentiated GnRH neurons may be a factor determining the ratio of phenotypically "inactive" versus "active" GnRH neurons during postnatal life.
Wierman
M E
ME
Department of Medicine, University of Colorado Health Science Center, Denver 80220, USA. margaret.wierman@uchsc.edu
Xiong
X
X
Kepa
J K
JK
Spaulding
A J
AJ
Jacobsen
B M
BM
Fang
Z
Z
Nilaver
G
G
Ojeda
S R
SR
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D050816:Octamer Transcription Factor-6; D010641:Phenotype; D010920:Placenta / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C494178:POU3F1 protein, human; C494179:Pou3f1 protein, rat; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D050816:Octamer Transcription Factor-6; D007987:Gonadotropin-Releasing Hormone; D004247:DNA