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XMRV inserts into CREB genes causing a mutation.
CREB is a "KING" regulatory gene is regulates other regulatory genes
Normal CREB function is essential to keep our brains working properly.
Downregulating the CREB gene can cause symptoms similar to Altzheimers or Huntington disease
CREB protects our neurons from environmental "nasties". Downregualtion of CREB is associated with cognitive decline in ageing.Creb is also essential for regulating the autonomic system.
Article
Nature Genetics 31, 47 - 54 (2002)
Published online: 22 April 2002; | doi:10.1038/ng882
Disruption of CREB function in brain leads to neurodegeneration
Theo Mantamadiotis1, 3, 4, Thomas Lemberger1, 4, Susanne C. Bleckmann1, Heidrun Kern1, Oliver Kretz1, Ana Martin Villalba1, Franois Tronche1, Christoph Kellendonk1, Daniel Gau1, Josef Kapfhammer2, Christiane Otto1, Wolfgang Schmid1 & Gnther Schtz1
1 Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
2 Institute of Anatomy, University of Basel, Switzerland.
3 Present address: Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, 3002, Australia.
4 These authors contributed equally to this work.
Correspondence should be addressed to Gnther Schtz g.schuetz@dkfz.de
Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem -/- background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.
and some more
Disruption of CREB function
Downloaded from www.jbc.org by guest, on April 24, 2010
4
specifically interferes with activity dependent synaptic plasticity ranging from long term
potentiation (LTP) to long-term memory (13-15). It is expected, therefore, that mechanisms that
interfere with CREB activation would compromise CREB activity dependent neuronal function
through disruption of downstream gene expression.
Brain-derived neurotrophic factor (BDNF) is one of the target genes of CREB (17,18).
BDNF, a member of the neurotrophin family, enhances survival, differentiation and growth of
certain neuronal populations, modulates synaptic activity and acts as an effector of neuronal
plasticity both during development and in the adult (20,21). BDNF participates in LTP, is
upregulated in the hippocampus during learning (22) and deficits in BDNF compromise LTP and
learning and memory (20). BDNF mRNA and protein are reduced in the hippocampus in AD
(23-25), a reduction proposed to contribute to cognitive decline observed in AD. Thus,
examination of BDNF transcription provides a means of assessment of effects on CREB
regulation, which may play a significant role in the pathogenesis of AD.
Here, we report that levels of Aβ1-42, which do not affect the survival of cortical neurons,
may indeed interfere with functions critical for neuronal plasticity, by eliciting a reduction of the
activity-dependent phosphorylation of CREB and the expression of BDNF, one of the important
target genes of this transcription factor.
Downloaded from www.jbc.org by guest, on April 24, 2010
CREB is a "KING" regulatory gene is regulates other regulatory genes
Normal CREB function is essential to keep our brains working properly.
Downregulating the CREB gene can cause symptoms similar to Altzheimers or Huntington disease
CREB protects our neurons from environmental "nasties". Downregualtion of CREB is associated with cognitive decline in ageing.Creb is also essential for regulating the autonomic system.
Article
Nature Genetics 31, 47 - 54 (2002)
Published online: 22 April 2002; | doi:10.1038/ng882
Disruption of CREB function in brain leads to neurodegeneration
Theo Mantamadiotis1, 3, 4, Thomas Lemberger1, 4, Susanne C. Bleckmann1, Heidrun Kern1, Oliver Kretz1, Ana Martin Villalba1, Franois Tronche1, Christoph Kellendonk1, Daniel Gau1, Josef Kapfhammer2, Christiane Otto1, Wolfgang Schmid1 & Gnther Schtz1
1 Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
2 Institute of Anatomy, University of Basel, Switzerland.
3 Present address: Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, 3002, Australia.
4 These authors contributed equally to this work.
Correspondence should be addressed to Gnther Schtz g.schuetz@dkfz.de
Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem -/- background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.
and some more
Disruption of CREB function
Downloaded from www.jbc.org by guest, on April 24, 2010
4
specifically interferes with activity dependent synaptic plasticity ranging from long term
potentiation (LTP) to long-term memory (13-15). It is expected, therefore, that mechanisms that
interfere with CREB activation would compromise CREB activity dependent neuronal function
through disruption of downstream gene expression.
Brain-derived neurotrophic factor (BDNF) is one of the target genes of CREB (17,18).
BDNF, a member of the neurotrophin family, enhances survival, differentiation and growth of
certain neuronal populations, modulates synaptic activity and acts as an effector of neuronal
plasticity both during development and in the adult (20,21). BDNF participates in LTP, is
upregulated in the hippocampus during learning (22) and deficits in BDNF compromise LTP and
learning and memory (20). BDNF mRNA and protein are reduced in the hippocampus in AD
(23-25), a reduction proposed to contribute to cognitive decline observed in AD. Thus,
examination of BDNF transcription provides a means of assessment of effects on CREB
regulation, which may play a significant role in the pathogenesis of AD.
Here, we report that levels of Aβ1-42, which do not affect the survival of cortical neurons,
may indeed interfere with functions critical for neuronal plasticity, by eliciting a reduction of the
activity-dependent phosphorylation of CREB and the expression of BDNF, one of the important
target genes of this transcription factor.
Downloaded from www.jbc.org by guest, on April 24, 2010