UMMS Affiliation

Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology

Date

8-22-2008

Document Type

Article

Subjects

Animals; Down-Regulation; Electric Stimulation; Electrophysiology; Growth Hormone; Hippocampus; Humans; Long-Term Potentiation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Protein Biosynthesis; Proteomics; Proto-Oncogene Proteins c-jun; RNA Precursors; RNA, Messenger; Recombinant Proteins; Synapses; Transcription Factors; Transcription, Genetic; mRNA Cleavage and Polyadenylation Factors

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Cytoplasmic polyadenylation element binding protein 1 (CPEB-1) resides at postsynaptic sites in hippocampal neurons in which it controls polyadenylation-induced translation. CPEB-1 knock-out (KO) mice display defects in some forms of synaptic plasticity and hippocampal-dependent memories. To identify CPEB-1-regulated mRNAs, we used proteomics to compare polypeptides in wild-type (WT) and CPEB-1 KO hippocampus. Growth hormone (GH) was reduced in the KO hippocampus, as were the GH signaling molecules phospho-JAK2 and phospho-STAT3. GH mRNA and pre-mRNA were reduced in the KO hippocampus, suggesting that CPEB-1 controls GH transcription. The transcription factor c-Jun, which binds the GH promoter, was also reduced in the KO hippocampus, as was its ability to coimmunoprecipitate chromatin containing the GH promoter. CPEB-1 binds c-Jun 3' untranslated region CPEs in vitro and coimmunoprecipitates c-Jun RNA in vivo. GH induces long-term potentiation (LTP) when applied to hippocampal slices from WT and CPEB-1 KO mice, but the magnitude of LTP induced by GH in KO mice is reduced. Pretreatment with GH did not reverse the LTP deficit observed in KO mice after theta-burst stimulation (TBS). Cordycepin, an inhibitor of polyadenylation, disrupted LTP induced by either GH application or TBS. Finally, GH application to hippocampal slices induced JAK2 phosphorylation in WT but not KO animals. These results indicate that CPEB-1 control of c-Jun mRNA translation regulates GH gene expression and resulting downstream signaling events (e.g., synaptic plasticity) in the mouse hippocampus.

Rights and Permissions

Citation: J Neurosci. 2008 Aug 20;28(34):8502-9. Link to article on publisher's site

DOI of Published Version

10.1523/JNEUROSCI.1756-08.2008

Related Resources

Link to Article in PubMed

Journal Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

PubMed ID

18716208

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.