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Differential Neuroendocrine Expression of Multiple Brain-Derived Neurotrophic Factor Transcripts

Department of Cellular Animal Physiology (A.H.K., B.A.d.R., E.W.R., B.G.J.), Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen, 6525 AJ Nijmegen, The Netherlands; Medical Service (G.H.), Veterans Affairs Northern California Health Care System, Martinez, California 94553; Department of Internal Medicine (G.H.), School of Medicine, University of California, Davis, Sacramento, California 95817; and Department of Biomolecular Chemistry (R.P.H.D., N.H.L.), Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Bruce G. Jenks, Department of Cellular Animal Physiology, Radboud University Nijmegen, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands. E-mail: b.jenks{at}science.ru.nl.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with important growth-promoting properties. We report here the first characterization of a BDNF gene in an amphibian, Xenopus laevis, and demonstrate that environmental factors can activate this gene in a promoter-specific fashion. The Xenopus BDNF gene contains six promoter-specific 5'-exons and one 3'-protein-encoding exon. We examined the expression of promoter-specific transcripts in Xenopus neuroendocrine melanotrope cells. These cells make a good model to study how environmental factors control gene expression. In animals placed on a black background melanotrope cells more actively produce and release MSH than in animals on a white background. BDNF is cosequestered and coreleased with MSH and stimulates biosynthesis of proopiomelanocortin (POMC), the precursor protein for MSH. Our analysis of the expression of the BDNF transcripts revealed that there is differential use of some BDNF promoters in melanotrope cells, depending on the adaptation state of the frog. During black-background adaptation, stimulation of expression of BDNF transcript IV preceded that of the POMC transcript, suggesting the BDNF gene is an effector gene for POMC expression. The possible mechanisms regulating expression of the various transcripts are discussed on the basis of the potential calcium- and cAMP-responsive elements in the promoter region of exon IV. Finally, we show that the upstream open reading frames of BDNF transcripts I and IV markedly decrease BDNF translation efficiency, giving the first indication for a functional role of untranslated BDNF exons.