The Groucho-related gene family regulates the gonadotropin-releasing hormone gene through interaction with the homeodomain proteins MSX1 and OCT1.
Gonadotropin-releasing hormone (GnRH) is exclusively expressed in a unique population of hypothalamic neurons that controls reproductive function. GnRH gene expression is highly dynamic. Its transcriptional activity is regulated in a complex spatiotemporal manner during embryonic development and postnatal life. Although a variety of transcription factors have been identified as regulators of GnRH transcription, most are promiscuous in their DNA-binding requirements, and none are solely expressed in GnRH neurons. Their specific activity is probably determined by interactions with distinct cofactors. Here we find that the Groucho-related gene (GRG) family of co-repressors is expressed in a model cell line for the GnRH neuron and co-expresses with GnRH during prenatal development. GRG proteins associate in vivo with the GnRH promoter. Furthermore, GRG proteins interact with two regulators of GnRH transcription, the homeodomain proteins MSX1 and OCT1. Co-transfection experiments indicate that GRG proteins regulate GnRH promoter activity. The long GRG forms enhance MSX1 repression and counteract OCT1 activation of the GnRH gene. In contrast, the short form, GRG5, has a dominant-negative effect on MSX1-dependent repression. Taken together, these data suggest that the dynamic switch between activation and repression of GnRH transcription is mediated by recruitment of the GRG co-regulators.
Rave-Harel
Naama
N
Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093-0674, USA.
Miller
Nichol L G
NL
Givens
Marjory L
ML
Mellon
Pamela L
PL
D000818:Animals; D002460:Cell Line; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D051957:MSX1 Transcription Factor; D046911:Macromolecular Substances; D051379:Mice; D005810:Multigene Family; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D050811:Octamer Transcription Factor-1; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D046911:Macromolecular Substances; C484084:Msx1 protein, mouse; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; C494166:Pou2f1 protein, mouse; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C499043:TLE1 protein, human; C434946:Tle1 protein, mouse; C434949:Tle4 protein, mouse; C089462:Tle5 protein, mouse; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone