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J Biol Chem, Vol. 274, Issue 2, 1078-1084, January 8, 1999

Brain-derived Neurotrophic Factor Expression in Vivo Is under the Control of Neuron-restrictive Silencer Element

Tnis Timmusk^§, Kaia Palm^§, Urban Lendahl^**, and Madis Metsis^§§

From the  Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden, the ^§ Department of Developmental Neuroscience, Biomedical Center, Uppsala University, S-751 23 Uppsala, Sweden, the ^** Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden, the  Center for Gene Technology, Tallinn Technical University, and the ^§§ Institute of Chemical Physics and Biophysics, Tallinn EE0026, Estonia

Neuron-restrictive silencer element (NRSE) has been identified in multiple neuron-specific genes. This element has been shown to mediate repression of neuronal gene transcription in nonneuronal cells. A palindromic NRSE (NRSE^BDNF) is present in the proximal region of brain-derived neurotrophic factor (BDNF) promoter II. Using in vitro binding assays, we establish that the upper half-site is largely responsible for the NRSE^BDNF activity. To delineate the in vivo role of NRSE in the regulation of rat BDNF gene, promoter constructs with intact and mutated NRSE^BDNF were introduced into transgenic mice. Our data show that NRSE^BDNF is controlling the activity of BDNF promoters I and II in the brain, thymus, and lung, i.e. in the tissues in which the intact reporter gene and endogenous BDNF mRNAs are expressed. Mutation of NRSE^BDNF did not lead to the ectopic activation of the reporter gene in any other nonneural tissues. In the brain, NRSE^BDNF is involved in the repression of basal and kainic acid-induced expression from BDNF promoters I and II in neurons. However, NRSE^BDNF does not control the activity of the BDNF gene in nonneuronal cells of brain.

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