CREB has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis.
Induction of specific gene expression patterns in response to activity confers functional plasticity to neurons. A principal role in the regulation of these processes has been ascribed to the cAMP responsive element binding protein (CREB). Using genome-wide expression profiling in mice lacking CREB in the forebrain, accompanied by deletion of the cAMP responsive element modulator gene (CREM), we here show that the role of these proteins in activity-induced gene expression is surprisingly selective and highly context dependent. Thus, only a very restricted subset of activity-induced genes (i.e., Gadd45b or Nr4a2) requires these proteins for their induction in the hippocampus after kainic acid administration, while they are required for most of the cocaine-induced expression changes in the striatum. Interestingly, in the absence of CREB, CREM is able to rescue activity-regulated transcription, which strengthens the notion of overlapping functions of the two proteins. In addition, we show that cholesterol metabolism is dysregulated in the brains of mutant mice, as reflected coordinated expression changes in genes involved in cholesterol synthesis and neuronal accumulation of cholesterol. These findings provide novel insights into the role of CREB and CREM in stimulus-dependent transcription and neuronal homeostasis.
Lemberger
Thomas
T
German Cancer Research Center, 69120 Heidelberg, Germany.
Parkitna
Jan Rodriguez
JR
Chai
Minqiang
M
Schütz
Günther
G
Engblom
David
D
D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051786:Cyclic AMP Response Element Modulator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic
C492004:Creb1 protein, mouse; C497411:Crem protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D051786:Cyclic AMP Response Element Modulator; D002784:Cholesterol; D007608:Kainic Acid