mRNA post-transcriptional regulation

mRNA post-transcriptional modifications DNA mRNA mRNA modifications synthesis folding and modifications sorting degradation

mRNA post-transcriptional modifications mRNA splicing mRNA editing miRNAs

mRNA splicing Splicing

mRNA splicing

Alternative splicing Blencowe, 2006. Cell

AChE alternative splicing during stress-situations

3’ alternative splicing 1 2 3 4 5 6 4’ GRE 500 bp AChE-S 1 2 3 4 6 3’ mRNA variants AChE-E 1 2 3 4 5 4’ AChE-R 1 2 3 4 5

AChE alternative splicing in stress

AChE-R is upregulated during stress Meshorer et al., 2005, Mol Psy Meshorer et al. 2002, Science

Post traumatic stress disorder DSM-IV diagnostic criteria for PTSD Model The person experiences a traumatic event Exposure to predator odor The traumatic event is persistently re-experienced Persistent avoidance of stimuli associated with the trauma Elevated maze Persistent symptoms of increased arousal Startle response

Post traumatic stress disorder Exposure to acute stressor

RNA editing RNA editing involves the insertion/deletion or modification of single nucleotides in pre-mRNA molecules The most widespread editing is A->I and C->U

RNA editing Keegan et al., 2001, Nat Gen Rev

RNA editing consequences Coding regions 5’ and 3’ UTRs Initiation and stop codons Splicing critical sites Keegan et al., 2001, Nat Gen Rev

A->I editing occurs predominantly in the CNS

5-HT receptor editing Toda et al. 2006. J. Pharm Sc.

5-HT editing induces functional alterations Herrick-Davis et al., 1999, J Neurochem

5-HT receptor editing and depression Serotonin has an important role in mood regulation The action of many antidepressant (TCA, SRI, XTC, cocaine) drugs is mediated by enhancement of 5-HT transmission. May low efficiency of 5-HT receptor, due to editing, be partially responsible of clinical depression?

5-HT editing and depression Englander et al., 2005, JNS Iwamoto et al., 2005, Neurosc Res

RNA interference (RNAi) Small RNA (sRNA) molecules hybridize mRNA impeding its translation These molecules are processed and act with respective protein complexes to bind their target mRNAs There are two precursor to sRNA: dsRNA and miRNA RNA templated polymerization hybridization of overlapping sequences endogenous transcripts dsRNA miRNA

A single miRNA is predicted to interact with hundreds of mRNA targets siRNA maturation A single miRNA is predicted to interact with hundreds of mRNA targets

Amplification of silencing Sijen et al. (2001) Cell

mIR-134 is expressed in the brain before synaptogenesis Schratt et al., Science 2006

mIR-134 regulates spine size Schratt et al., Science 2006

mIR-134 interacts with Limk1 Schratt et al., Science 2006

mIR-134 suppresses Limk1 expression Schratt et al., Science 2006

Limk1 rescues miRNA-134 induced spine volume reduction Schratt et al., Science 2006

BDNF controls miRNA-134 effect on neurite growth Schratt et al., Science 2006