Disruption of CREB function in brain leads to neurodegeneration.
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.
Mantamadiotis
Theo
T
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Lemberger
Thomas
T
Bleckmann
Susanne C
SC
Kern
Heidrun
H
Kretz
Oliver
O
Martin Villalba
Ana
A
Tronche
François
F
Kellendonk
Christoph
C
Gau
Daniel
D
Kapfhammer
Josef
J
Otto
Christiane
C
Schmid
Wolfgang
W
Schütz
Günther
G
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; C097188:polyglutamine