TALE Homeodomain Proteins Regulate Gonadotropin-releasing Hormone Gene Expression Independently and via Interactions with Oct-1

Abstract

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproductive function. Expression of the GnRH gene is confined to a rare population of neurons scattered throughout the hypothalamus. Restricted expression of the rat GnRH gene is driven by a multicomponent enhancer and an evolutionarily conserved promoter. Oct-1, a ubiquitous POU homeodomain transcription factor, was identified as an essential factor regulating GnRH transcription in the GT1-7 hypothalamic neuronal cell line. In this study, we conducted a two-hybrid interaction screen in yeast using a GT1-7 cDNA library to search for specific Oct-1 cofactors. Using this approach, we isolated Pbx1b, a TALE homeodomain transcription factor that specifically associates with Oct-1. We show that heterodimers containing Pbx/ Prep1 or Pbx/Meis1 TALE homeodomain proteins bind to four functional elements within the GnRH regulatory region, each in close proximity to an Oct-1-binding site. Cotransfection experiments indicate that TALE proteins are essential for GnRH promoter activity in the GT1-7 cells. Moreover, Pbx1 and Oct-1, as well as Prep1 and Oct-1, form functional complexes that enhance GnRH gene expression. Finally, Pbx1 is expressed in GnRH neurons in embryonic as well as mature mice, suggesting that the associations between TALE homeodomain proteins and Oct-1 regulate neuron-specific expression of the GnRH gene in vivo.

Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb

“…In the hindbrain, the PBC proteins Pbx1-4 and members of the Hox clusters are major Meis-binding partners (Elkouby et al, 2012;Maeda et al, 2002;Vlachakis et al, 2001;Wassef et al, 2008), but only a few proteins are known to associate with Meis family proteins in the mes-, di-or telencephalon. These include Oct1 (Slc22a1), which cooperates with the Meis-related Prep1 (Pknox1) to control expression of gonadotropin-releasing hormone in the hypothalamus, and Otx2, Pax3 and Pax7 during tectal development (Agoston and Schulte, 2009;Agoston et al, 2012;Rave-Harel et al, 2004). The findings reported here now identify Pax6 and Dlx2 as Meis-interacting proteins in the forebrain.…”

Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression

“…Eight of these 10 motifs are underrepresented in female-specific GH-responsive sites (cluster A 1 ). These 10 motifs include binding sites for CUX2, a highly female-specific, GH-regulated transcription factor (24), GFI1, a STAT-inducible transcriptional repressor (22,60), OCT1 (POU2F1), which interacts with STAT5 in binding to the cyclin D1 promoter (31), PBX1, which interacts with OCT1 (35,48) and may help penetrate repressive chromatin (41), and EVI1 (corresponding to the gene Mecom), a positive regulator of PBX1 (44) that interacts with the histone methyltransferase SUV39H1 (13). Two motifs, binding sites for MYC and MAX, were enriched in male-specific DHS sites not responsive to GH.…”

Developmental Regulation of Gonadotropin-releasing Hormone Gene Expression by the MSX and DLX Homeodomain Protein Families

“…Investigation of immature, migratory and adult GnRH-expressing neurons has revealed differences in the expression pattern of transcriptional factors that regulate spatiotemporal transcriptional control of the GnRH gene (45,46). Thus, GnRH neurons are a heterogeneous population that differentially expresses specific genes at distinct stages of embryonic development, which may, in turn, result in dynamic regulation of GnRH promoter expression.…”