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
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