January 1, 1999Journal of Biological Chemistry120 citationsOpen Access

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

TTTõnis Timmusk KPKaia Palm ULUrban Lendahl

Key Points

Key points are not available for this paper at this time.

Abstract

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 (NRSEBDNF) 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 NRSEBDNF activity. To delineate the in vivorole of NRSE in the regulation of rat BDNF gene, promoter constructs with intact and mutated NRSEBDNF were introduced into transgenic mice. Our data show that NRSEBDNF 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 NRSEBDNF did not lead to the ectopic activation of the reporter gene in any other nonneural tissues. In the brain, NRSEBDNF is involved in the repression of basal and kainic acid-induced expression from BDNF promoters I and II in neurons. However, NRSEBDNF does not control the activity of the BDNF gene in nonneuronal cells of brain. 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 (NRSEBDNF) 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 NRSEBDNF activity. To delineate the in vivorole of NRSE in the regulation of rat BDNF gene, promoter constructs with intact and mutated NRSEBDNF were introduced into transgenic mice. Our data show that NRSEBDNF 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 NRSEBDNF did not lead to the ectopic activation of the reporter gene in any other nonneural tissues. In the brain, NRSEBDNF is involved in the repression of basal and kainic acid-induced expression from BDNF promoters I and II in neurons. However, NRSEBDNF does not control the activity of the BDNF gene in nonneuronal cells of brain. Neurotrophins (NTs) 1The abbreviations used are: NT, neurotrophin; BDNF, brain-derived neurotrophic factor; bp, base pair(s); kb, kilobase pair(s); NRSF, neuron-restrictive silencer factor; EMSA, electrophoretic mobility shift assay; nACh, nicotinic acetylcholine receptor; NaCh, sodium channel; mut, mutant; CAT, chloramphenicol acetyltransferase; RPA, RNase protection assay; KA, kainic acid; RE, repressor element; REST, RE-1 silencing transcription factor. 1The abbreviations used are: NT, neurotrophin; BDNF, brain-derived neurotrophic factor; bp, base pair(s); kb, kilobase pair(s); NRSF, neuron-restrictive silencer factor; EMSA, electrophoretic mobility shift assay; nACh, nicotinic acetylcholine receptor; NaCh, sodium channel; mut, mutant; CAT, chloramphenicol acetyltransferase; RPA, RNase protection assay; KA, kainic acid; RE, repressor element; REST, RE-1 silencing transcription factor. are secreted polypeptides that regulate the survival of selective populations of developing neurons and maintenance of the characteristic functions of mature neurons (1Bothwell M. Annu. Rev. Neurosci. 1995; 18: 223-253Crossref PubMed Scopus (764) Google Scholar, 2Levi-Montalcini R. Science. 1987; 237: 1154-1162Crossref PubMed Scopus (2687) Google Scholar, 3Lewin G.R. Barde Y.-A. Annu. Rev. Neurosci. 1996; 19: 289-317Crossref PubMed Scopus (1779) Google Scholar). The family of NTs includes nerve growth factor, brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5. Each factor is differentially involved in neurogenesis as well as in neuronal adaptive responses, implying well controlled regulatory mechanisms underlying their expression. Multipromoter structure, common to NT genes (4Bishop J.F. Mueller G.P. Mouradian M.M. Mol. Brain Res. 1994; 26: 225-232Crossref PubMed Scopus (63) Google Scholar, 5Leingärtner A. Lindholm D. Eur. J. Neurosci. 1994; 6: 1149-1159Crossref PubMed Scopus (51) Google Scholar, 6Nakayama M. Gahara Y. Kitamura T. Ohara O. Mol. Brain Res. 1994; 21: 206-218Crossref PubMed Scopus (77) Google Scholar, 7Salin T. Timmusk T. Lendahl U. Metsis M. Mol. Cell Neurosci. 1997; 9: 264-275Crossref PubMed Scopus (19) Google Scholar, 8Timmusk T. Palm K. Metsis M. Reintam T. Paalme V. Saarma M. Persson H. Neuron. 1993; 10: 475-489Abstract Full Text PDF PubMed Scopus (725) Google Scholar), has apparently evolved to confer complex regulation of their expression. We have previously shown that four promoters direct tissue-specific expression of the rat BDNF gene (8Timmusk T. Palm K. Metsis M. Reintam T. Paalme V. Saarma M. Persson H. Neuron. 1993; 10: 475-489Abstract Full Text PDF PubMed Scopus (725) Google Scholar). Promoter IV is active in nonneural tissues (lung, heart, and muscle), whereas promoters I, II, and III are predominantly used in the brain and regulated by glutamatergic and GABAergic neurotransmitter systems (8Timmusk T. Palm K. Metsis M. Reintam T. Paalme V. Saarma M. Persson H. Neuron. 1993; 10: 475-489Abstract Full Text PDF PubMed Scopus (725) Google Scholar, 9Metsis M. Timmusk T. Arenas E. Persson H. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8802-8806Crossref PubMed Scopus (204) Google Scholar). Recent studies have shown that changes in BDNF expression are linked to synaptic plasticity during development (10Cellerino A. Maffei L. Prog. Neurobiol. 1996; 49: 53-71Crossref PubMed Google Scholar, 11Katz L.C. Shatz C.J. Science. 1996; 274: 1133-1138Crossref PubMed Scopus (2373) Google Scholar) and also to the process of memory and learning (12Berninger B. Poo M.M. Curr. Opin. Neuorbiol. 1996; 6: 324-330Crossref PubMed Scopus (160) Google Scholar, 13Bonhoeffer T. Curr. Opin. Neurobiol. 1996; 6: 119-126Crossref PubMed Scopus (266) Google Scholar, 14Lo D.C. Neuron. 1995; 15: 979-981Abstract Full Text PDF PubMed Scopus (244) Google Scholar, 15Thoenen H. Science. 1995; 270: 593-598Crossref PubMed Scopus (1715) Google Scholar). Mice heterozygous for BDNF gene null-mutation have severe impairment in hippocampal long term potentiation (16Korte M. Carroll P. Wolf E. Brem G. Thoenen H. Bonhoeffer T. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8856-8860Crossref PubMed Scopus (1201) Google Scholar, 18Patterson S.L. Abel T. Deuel T.A.S. Martin K.S. Rose J.C. Kandel E.R. Neuron. 1996; 16: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (1033) Google Scholar) and in normal spatial learning (19Linnarson S. Björklund A. Ernfors P. Eur. J. Neurosci. 1998; 9: 2581-2587Crossref Scopus (403) Google Scholar). An inverted repeat within the first intron of rat BDNF gene shows substantial similarity to the neuron-restrictive silencer element (NRSE). NRSE, also known as repressor element-1 (RE1), has been defined as a negative-acting DNA regulatory element to prevent the expression of neuronal genes in nonneuronal cell types or in inappropriate neuronal subtypes (20Kraner S.D. Chong J.A. Tsai H.J. Mandel G. Neuron. 1992; 9: 37-44Abstract Full Text PDF PubMed Scopus (283) Google Scholar, 21Mori N. Schoenherr C. Vandenbergh D.J. Anderson D.J. Neuron. 1992; 9: 45-54Abstract Full Text PDF PubMed Scopus (346) Google Scholar, 22Schoenherr C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar). The first evidence that NRSE is able to mediate repression of transcription came from the analysis of the promoters of rat SCG10 (21Mori N. Schoenherr C. Vandenbergh D.J. Anderson D.J. Neuron. 1992; 9: 45-54Abstract Full Text PDF PubMed Scopus (346) Google Scholar) and rat type II sodium channel (NaChII) (20Kraner S.D. Chong J.A. Tsai H.J. Mandel G. Neuron. 1992; 9: 37-44Abstract Full Text PDF PubMed Scopus (283) Google Scholar) genes. To date, several studies have that present in the regulatory of multiple neuronal are for their neuron-specific expression G. J. 1998; Full Text Full Text PDF PubMed Scopus (51) Google Scholar, L. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, P. S. J. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. S. S. Mol. Brain Res. 1997; PubMed Scopus Google Scholar, P. Schoenherr C.J. Anderson J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. G. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. Anderson D.J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). The of a that the neuron-restrictive silencer factor C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar), also known as RE-1 silencing transcription factor J.A. S. Y. S.D. Mandel G. 1995; Full Text PDF PubMed Scopus Google Scholar), is a of the family of transcription The factor, as identified to to the of the complex II gene, and activity in the T. S. J. 1996; Google Scholar). is in nonneural tissues development C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google J.A. S. Y. S.D. Mandel G. 1995; Full Text PDF PubMed Scopus Google Scholar, T. S. J. 1996; Google Scholar). In the are in the neuronal C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar, J.A. S. Y. S.D. Mandel G. 1995; Full Text PDF PubMed Scopus Google Scholar) and during Our data that expression also in the neurons of brain K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). The present mechanisms underlying BDNF gene the of the palindromic NRSE (NRSEBDNF) in the proximal region of promoter II. We have previously shown that BDNF gene promoter I, promoter II, and endogenous BDNF expression in transgenic T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar). we have transgenic the BDNF promoter with in the NRSEBDNF and that the regulation of BDNF gene in is the control of chloramphenicol RNase protection were as (8Timmusk T. Palm K. Metsis M. Reintam T. Paalme V. Saarma M. Persson H. Neuron. 1993; 10: 475-489Abstract Full Text PDF PubMed Scopus (725) Google Scholar, T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google N. G. G. R. K. J. 1997; PubMed Scopus Google Scholar). A BDNF II and into and a the Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Mutation of NRSE in the in the are shown in the the mutated NRSE used to the as for T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar). were and for as previously T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar). were analysis with a T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google BDNF (8Timmusk T. Palm K. Metsis M. Reintam T. Paalme V. Saarma M. Persson H. Neuron. 1993; 10: 475-489Abstract Full Text PDF PubMed Scopus (725) Google Scholar) by the of BDNF in the to that in the transgenic with and transgenic were used in in and the were or the were by the of and were as Res. 19: PubMed Scopus Google Scholar). shift were as A. K. Palm K. Metsis M. T. Mol. 1995; 15: PubMed Scopus Google Scholar). to the and element and to the NRSE of rat type II sodium channel gene (20Kraner S.D. Chong J.A. Tsai H.J. Mandel G. Neuron. 1992; 9: 37-44Abstract Full Text PDF PubMed Scopus (283) Google Scholar) and rat SCG10 gene (21Mori N. Schoenherr C. Vandenbergh D.J. Anderson D.J. Neuron. 1992; 9: 45-54Abstract Full Text PDF PubMed Scopus (346) Google Scholar) were used as In the of is as In the used The inverted repeat (NRSEBDNF) in the proximal region of BDNF promoter II is of The element has with the NRSE C.J. Anderson D.J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar), whereas the element shows to The of and have that not of the NRSE are for regulatory transcription C.J. Anderson D.J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). introduced to of the have been to for the silencing activity of NRSE (20Kraner S.D. Chong J.A. Tsai H.J. Mandel G. Neuron. 1992; 9: 37-44Abstract Full Text PDF PubMed Scopus (283) Google Scholar, 21Mori N. Schoenherr C. Vandenbergh D.J. Anderson D.J. Neuron. 1992; 9: 45-54Abstract Full Text PDF PubMed Scopus (346) Google Scholar). In the upper element of the in the are with the and in the show that in NRSEBDNF have the to mediate To inverted element in the regulation of BDNF gene, were and in transgenic mice. Our studies that a BDNF promoters I and II the tissue-specific of the reporter gene expression T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar). In the present we the intact NRSEBDNF in the with the and introduced the into mice. were and of were to transgenic for In activity the in the brain, whereas the of activity were in and of activity in brain in the of expression from to the of activity were in the and the spatial expression of the reporter gene in from the expression in we that of NRSEBDNF is not to ectopic expression from BDNF promoters I and II in tissues that not the intact promoter and also endogenous BDNF However, in the of reporter gene expression were in transgenic with the mutated promoter as with the the intact promoter In the brain, thymus, and activity and activity in transgenic mutated as with in any of the intact reporter The of activity in the and of were as with the of activity in and of In the brain, the brain of activity in transgenic with as with activity in In the which the of the reporter gene expression in the brain, activity in transgenic with in with The in activity in the to the transgenic with as with the data that NRSEBDNF is controlling the activity of BDNF promoters I and II in the brain, thymus, and were to establish NRSEBDNF of BDNF I and of BDNF II the activity of BDNF promoter I, promoter II, or The analysis that in the mRNAs with BDNF I were and mRNAs with BDNF II as with the in the with intact promoter of the of in and were and the of were as with the in data that of NRSEBDNF the activity of BDNF promoter I and promoter II and to the expression from studies that NRSE is to prevent expression of neuronal genes in nonneural tissues and cell populations C.J. Anderson D.J. Curr. Opin. Neurobiol. 1995; PubMed Scopus Google Scholar). we of expression and activity in the brain of from the ectopic activation of the in nonneuronal cells. Using in expression in of with the intact promoter In to the expression of in with promoter In transgenic with expression the in the neurons of the region and of in the neuronal in the intact or the mutated promoter we that NRSEBDNF is not the expression to of neurons and data not Mutation of NRSEBDNF did not lead to the ectopic expression of in nonneuronal cell populations of brain. Our data that the neurons of of BDNF expression from promoters I and II BDNF with I were whereas with II were M. Timmusk T. Arenas E. Persson H. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8802-8806Crossref PubMed Scopus (204) Google Scholar). We have also shown that the expression from promoters I and II T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar). data that are present in the BDNF region of To NRSEBDNF involved in the regulation of BDNF gene, we the expression of in the of transgenic with the intact or mutated promoter constructs Using in a in expression in the neurons of and in the neurons of region in of with and in with In the in expression were in any of of were in neurons in of with analysis that in the of with the intact promoter expression whereas in the the and of and data not by in from the expression and also from the of neurons to control in the of and as by not data that in the neurons of the of BDNF from promoters I and II is the control of repression of the expression in the neurons of of and endogenous BDNF in the and and and The of were to the of endogenous BDNF and to the of from the of transgenic from the of transgenic we of NRSEBDNF are for activity within and the analysis several that tissue-specific of that the complex with a of to the upper element The element to a The of not to complex and a of to the complex not data that the and that the upper element of NRSEBDNF is for activity in studies have shown that the transcription factor is in nonneural tissues C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar, J.A. S. Y. S.D. Mandel G. 1995; Full Text PDF PubMed Scopus Google Scholar, T. S. J. 1996; Google Scholar, K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). we activity is present in the complex from A of the NRSE of and SCG10 genes not in the of the complex that for the factor as does the upper element of other studies have shown that and and a complex with in analysis C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar, C.J. Anderson D.J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, J.A. S. Y. S.D. Mandel G. 1995; Full Text PDF PubMed Scopus Google Scholar, K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). we that the complex from The as did not any with of any of the to the Using cell of analysis is whereas complex to the complex from the studies of complex that complex with the of of the element of NRSEBDNF and not with the of and A of to complex and data not also from other of brain and not data that complex is a complex that the element of NRSEBDNF and does not several NRSE not complex by with the NRSEBDNF studies of the of the complex that the element of NRSEBDNF is by transcription a of to the of complex the half-site of NRSEBDNF which is also with other of did not complex in This that of the family as and are not involved in the of complex not Using from and other brain a complex with mobility and to complex and data not show that binding been in as with the a of with the NRSEBDNF for the binding of complex from data that introduced to the NRSEBDNF have substantial the of complex We have previously shown that expression in the neurons of of brain K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). is that complex are in hippocampal the NRSE with and that or to Using the of the NRSEBDNF and of the to complex we to a complex studies that of a of to the of complex and not complex A of the of We have previously shown that the NRSE of NRSEBDNF with the NRSEBDNF for the binding of K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). data that the complex which is from the of and is by the upper of NRSEBDNF and other NRSE and data not An of the of complex did not the of complex NRSEBDNF with that the introduced to the NRSEBDNF with binding activity in the brain. The of to the of NRSEBDNF in the regulation of BDNF gene expression. The of data are as the activity of BDNF promoters I and II in the brain, thymus, and not in other in the brain, NRSEBDNF the activity of BDNF promoters I and II in neurons and has in nonneuronal NRSEBDNF is involved in the repression of the activation of BDNF promoters I and II in populations of neurons in the the palindromic NRSEBDNF in the proximal region of BDNF promoter II is of binding the element is largely responsible for the activity of NRSEBDNF in the as well as in the brain. neuronal and a nonneuronal genes in their regulatory C.J. Anderson D.J. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar), a common underlying their expression. studies have used expression in cell and that NRSE as a silencer in nonneuronal cell types (20Kraner S.D. Chong J.A. Tsai H.J. Mandel G. Neuron. 1992; 9: 37-44Abstract Full Text PDF PubMed Scopus (283) Google Scholar, 21Mori N. Schoenherr C. Vandenbergh D.J. Anderson D.J. Neuron. 1992; 9: 45-54Abstract Full Text PDF PubMed Scopus (346) Google Scholar, G. J. 1998; Full Text Full Text PDF PubMed Scopus (51) Google Scholar, L. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, P. S. J. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, P. Schoenherr C.J. Anderson J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. G. J. 1996; Full Text Full Text PDF PubMed Scopus Google H. K.S. Mol. Brain Res. 1995; PubMed Scopus Google Scholar, J. E. J. 1995; PubMed Scopus Google Scholar). mechanisms of silencing are largely A which to the family of transcription and shows a predominantly nonneural expression has been to to NRSE and mediate repression in expression C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar, J.A. S. Y. S.D. Mandel G. 1995; Full Text PDF PubMed Scopus Google Scholar, T. S. J. 1996; Google Scholar, K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). Our transgenic studies to the of NRSEBDNF in the regulation of BDNF gene in Our data show that in nonneural of NRSEBDNF in of the expression in and endogenous promoters I and II, are active T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar). of reporter gene expression not in any other nonneural tissues. we that NRSEBDNF to the regulation of BDNF gene in and However, of element is not to the expression from BDNF promoters I and II in other nonneural tissues. This that the of BDNF gene in tissues is the of or complex of regulatory transgenic studies have the of the tissue-specific gene Mutation of NRSE in the rat promoter to expression of the in a nonneural tissues J.C. M. Res. 1994; PubMed Scopus Google Scholar). Recent transgenic studies of the regulation of the cell gene that in nonneural NRSE controlling ectopic expression from promoter during development P. J. Cell 1997; PubMed Scopus Google P. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). In with that in NRSE is not to the of a neuronal gene in the of nonneural tissues. The of also that NRSEBDNF gene expression in of to of expression in the neurons of brain, in the region of and are and not the of element as a neuron-restrictive gene expression within the have also been by transgenic transgenic studies of the rat promoter that of NRSE with a to the expression of the in the brain J.C. M. Res. 1994; PubMed Scopus Google Scholar). A transgenic of the neuronal nicotinic acetylcholine promoter that of a in the NRSE to or expression in of the developing A. N. L. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). analysis of promoter that within the linked to a and a in the brain, of the NRSE to of promoter activity in and whereas in the promoter activity P. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). data with that NRSE is for the basal expression of several neuronal genes within the and that are the In we show that of the of NRSEBDNF did not transcription from BDNF promoters I or II in the nonneuronal cells of brain. In with of NRSE in the promoter did not lead to the ectopic reporter gene expression in or other nonneuronal cells of brain A. N. L. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). In of NRSE from promoter in the ectopic reporter gene expression in the the and in the P. J. Cell 1997; PubMed Scopus Google Scholar). The of NRSE to nonneural expression of and not other and neuronal genes that NRSE in regulatory and that the with other regulatory is for NRSE to gene regulation in cells. regulation of the and BDNF genes in nonneuronal cells is the control of that binding for other of K. T. A. S. A. C. 1997; PubMed Google Scholar) or M. E. 1996; PubMed Google Scholar) transcription to control neuronal genes in nonneuronal cells and prevent nonneuronal cells from neuronal Our data also establish that which is of BDNF I and of BDNF II, the activity of BDNF promoter I and promoter II. of complex II genes have that within the which similarity with NRSE, also lead to activity of the the element is in to the transcription T. S. J. 1996; Google Scholar, S.L. J. 1992; Google Scholar) the other has been that NRSE functions as or from the as a silencer A. N. L. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). The that the NRSE does not have to to the promoter to as a NRSE present of the promoter as in cell populations P. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). data that largely the promoter BDNF, other is known to in during and changes in expression are P. R. 1994; PubMed Scopus Google Scholar, C. 1994; Full Text PDF PubMed Scopus Google Scholar). is evidence that BDNF expression in the is by glutamatergic activation D.C. Neuron. 1995; 15: 979-981Abstract Full Text PDF PubMed Scopus (244) Google Scholar, 15Thoenen H. Science. 1995; 270: 593-598Crossref PubMed Scopus (1715) Google Scholar, H. Science. 1995; 267: PubMed Scopus Google Scholar). in BDNF expression in hippocampal and neurons of activity are with long term potentiation in J.C. T. L. K. H. D. and in the of and their Scholar), or in O. E. J. M. T. L. K. H. D. and in the of and their Scholar), we NRSEBDNF is a within the BDNF gene that to any of Our present that NRSEBDNF is involved in the repression of the activation of BDNF promoters I and II in neuronal populations of the studies have the mechanisms underlying BDNF gene regulation by glutamatergic have been identified that mediate of BDNF expression in the neurons of brain in T. Lendahl U. H. Arenas E. Persson H. Metsis M. J. Cell 1995; PubMed Scopus Google Scholar) and in the neuronal vitro Mol. Brain Res. 1997; PubMed Scopus Google Scholar). involved in the of BDNF gene in cells have also been J.F. G. Mueller G.P. Mouradian M.M. Mol. Brain Res. 1997; PubMed Scopus Google Scholar). II and IV have been shown to involved in the regulation of the expression of BDNF in Eur. J. Neurosci. 1998; 10: PubMed Scopus (19) Google Scholar). identified that a element and a element within the proximal region of BDNF promoter III mediate the of BDNF gene in hippocampal and neurons K. Timmusk T. A. Neuron. 1998; Full Text Full Text PDF PubMed Scopus Google S. Neuron. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The present is the first to that element within the BDNF gene (NRSEBDNF) is in the regulation of of BDNF promoters I and II to the changes in neuronal activity. NRSEBDNF of as inverted studies have shown that NRSEBDNF and upper in vitro C.J. Anderson D.J. Science. 1995; 267: 1360-1363Crossref PubMed Scopus (926) Google Scholar, K. N. Metsis M. Timmusk T. J. Neurosci. 1998; 15: Google Scholar). The of that the is largely responsible for the in the and brain, and complex repression of transcription from BDNF promoters I and II. vitro binding data that the half-site is a of that also have the binding activity. The of the element in the regulation of BDNF gene in to NRSEBDNF and regulation to mediate repression and of expression from BDNF promoters I and II. We are to for the of the We and for

KI fragen

Bookmark

View Full Paper

Cite This Study

Timmusk et al. (Fri,) studied this question.

synapsesocial.com/papers/6a5f735941a6873424598efa https://doi.org/https://doi.org/10.1016/s0021-9258(19)88378-3

KI fragen

Bookmark

View Full Paper