1. mRNA post-transcriptional regulation

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

3. mRNA post-transcriptional modifications
mRNA splicing
mRNA editing
miRNAs

4. mRNA splicing
Splicing

5. mRNA splicing

6. Alternative splicing
Blencowe, Cell

7. AChE alternative splicing during stress-situations

8. 3’ alternative splicing1 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

9. AChE alternative splicing in stress

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

11. 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

12. Post traumatic stress disorder
Exposure to acute
stressor

13. 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

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

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

16. A->I editing occurs predominantly in the CNS

17. 5-HT receptor editing
Toda et al J. Pharm Sc.

18. 5-HT editing induces functional alterations
Herrick-Davis et al., 1999, J Neurochem

19. 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?

20. 5-HT editing and depression
Englander et al., 2005, JNS
Iwamoto et al., 2005, Neurosc Res

21. 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

22. 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

23. Amplification of silencing
Sijen et al. (2001) Cell

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

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

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

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

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

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