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Originally published In Press as doi:10.1074/jbc.M007097200 on September 19, 2000

J. Biol. Chem., Vol. 275, Issue 50, 39662-39670, December 15, 2000
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Myocyte Enhancer Factors-2B and -2C Are Required for Adhesion Related Kinase Repression of Neuronal Gonadotropin Releasing Hormone Gene Expression*

Melissa P. AllenDagger §, Mei XuDagger §, Chan ZengDagger §, Stuart A. Tobet, and Margaret E. WiermanDagger §||**

From the Dagger  Department of Medicine and || Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, the § Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, and the  Program in Neuroscience, The Shriver Center, Harvard Medical School, Waltham, Massachusetts 02452

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.


* This work was supported by National Institute of Child Health and Human Development Grants HD31191-03 (to M. E. W.), HD33441 (to G. Schwarting and S. A. T.), and a Lalor Fellowship (to M. P. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Veterans Affairs Medical Center, Box 111H, 1055 Clermont St., Denver, CO 80220. Tel: 303-399-8020 (ext. 3137); Fax: 303-393-5271; E-mail: margaret.wierman@uchsc.edu.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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