Myocyte enhancer factors-2B and -2C are required for adhesion related kinase repression of neuronal gonadotropin releasing hormone gene expression.
Synthesis of the hypothalamic peptide, gonadotropin releasing hormone (GnRH), is paramount for reproductive function. GnRH neurons originate in the olfactory region and migrate into the forebrain during development. We recently implicated adhesion related kinase (Ark) in GnRH neuron development based on its differential expression in two GnRH producing cell lines, GT1-7 and Gn10. The Ark membrane receptor encodes an extracellular domain resembling cell adhesion molecules and an intracellular tyrosine kinase. Ark is expressed in Gn10 cells derived from migrating GnRH neurons but not GT1-7 cells of the post-migratory phenotype. Here, we show that Ark and GnRH transcripts are colocalized in the cribriform plate at midgestation, suggesting that Ark is expressed in migrating GnRH neurons in vivo. Furthermore, we have identified the GnRH gene as a downstream target of Ark signaling. Ark inhibits GnRH gene expression in GnRH neuronal cells via the coordinated binding of myocyte enhancer factor-2B and -2C (MEF-2B and -2C) and a putative homeoprotein within the proximal rat GnRH promoter. Given that MEF-2 proteins are widely expressed in the brain, these studies provide further evidence for MEF-2 action during neuronal development. Moreover, our studies elucidate a potential role for Ark in regulating GnRH gene expression during GnRH neuronal migration.
Allen
M P
MP
Department of Medicine and Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Xu
M
M
Zeng
C
C
Tobet
S A
SA
Wierman
M E
ME
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D005799:Genes, Dominant; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D015513:Oncogene Proteins; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D011518:Proto-Oncogene Proteins; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000094963:Axl Receptor Tyrosine Kinase
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase