mRNA post-transcriptional regulation

synthesis folding and modifications

sortingdegradation

DNA

mRNA

mRNA post-transcriptional modifications

mRNA modifications

mRNA post-transcriptional modifications

mRNA splicingmRNA editingmiRNAs

mRNA splicing

Splicing

mRNA splicing

Alternative splicing

Blencowe, 2006. Cell

AChE alternative splicing AChE alternative splicing during stress-situationsduring stress-situations

1 2 3 4 5

AChE-EAChE-E

1 2 3 4 5

4’

AChE-RAChE-R

1 2 3 4 6

AChE-SAChE-S

1 2 3 4 5 6

4’

GRE500 bp

3’ alternative splicing

3’ mRNA3’ mRNAvariantsvariants

AChE alternative splicing in stressAChE alternative splicing in stress

AChE-R is upregulated during AChE-R is upregulated during stressstress

Meshorer et al. 2002, ScienceMeshorer et al., 2005, Mol Psy

Post traumatic stress disorderPost traumatic stress disorder

DSM-IV diagnostic criteria for PTSD

•The person experiences a traumatic event

•The traumatic event is persistently re-experienced

•Persistent avoidance of stimuli associated with the trauma

•Persistent symptoms of increased arousal

Model

Exposure to predator odor

Elevated maze

Startle response

Exposure to acutestressor

Post traumatic stress disorderPost traumatic stress disorder

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 regions5’ and 3’ UTRsInitiation and stop codonsSplicing 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

Iwamoto et al., 2005, Neurosc ResEnglander et al., 2005, JNS

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 interference (RNAi)

miRNAdsRNA

RNA templated

polymerization

hybridization of overlapping sequences

endogenous transcripts

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