title: Otx2 induction of the gonadotropin-releasing hormone promoter is modulated by direct interactions with Grg co-repressors.
abstract: Hormonal communication between the hypothalamus, pituitary, and gonads orchestrates the development and regulation of mammalian reproductive function. In mice, gonadotropin-releasing hormone (GnRH) expression is limited to approximately 1000 neurons that originate in the olfactory placode then migrate to specific positions scattered throughout the hypothalamus. Coordination of the hypothalamic-pituitary-gonadal axis is dependent upon correct migration of GnRH neurons into the hypothalamus followed by the appropriate synthesis and pulsatile secretion of GnRH. Defects in any one of these processes can cause infertility. Recently, substantial progress has been made in identifying transcription factors, and their cofactors, that regulate not only adult expression of GnRH, but also the maturation of GnRH neurons. Here, we show that expression of Otx2, a homeodomain protein required for the formation of the forebrain, is dramatically up-regulated during GnRH neuronal maturation and that overexpression of Otx2 increases GnRH promoter activity in GnRH neuronal cell lines. Furthermore, Otx2 transcriptional activity is modulated by Grg4, a member of the Groucho-related-gene (Grg) family. Using mutational analysis, we show that a WRPW peptide motif within the Otx2 protein is required for physical interaction between Otx2 and Grg4. Without this physical interaction, Grg4 cannot repress Otx2-dependent activation of GnRH gene transcription. Taken together, these data show that Otx2 is important for GnRH expression and that direct interaction between Otx2 and Grg co-repressors regulates GnRH gene expression in hypothalamic neurons.
authors.affiliation: From the Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674.
authors.forename: Rachel
authors.initials: R
authors.lastname: Larder
authors.affiliation: From the Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674. Electronic address: pmellon@ucsd.edu.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D056970:Co-Repressor Proteins; D017931:DNA Primers / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D051857:Otx Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D056970:Co-Repressor Proteins; D017931:DNA Primers; D051857:Otx Transcription Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; C434949:Tle4 protein, mouse; C089462:Tle5 protein, mouse; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone