Kelly Gu & Jackie Tsao AMYLOID PRECURSOR PROTEIN REGULATES NEUROGENESIS BY ANTAGONIZING MIR-574-5P...
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Transcript of Kelly Gu & Jackie Tsao AMYLOID PRECURSOR PROTEIN REGULATES NEUROGENESIS BY ANTAGONIZING MIR-574-5P...
Kelly Gu & Jackie Tsao
AMYLOID PRECURSOR PROTEIN REGULATES NEUROGENESIS BY
ANTAGONIZING MIR-574-5P IN THE DEVELOPING CEREBRAL CORTEX
Defining APPDefining miRNAPurposeSetup: Why miR-574-5p?Connection b/w APP and miRNAmiRnA-574-5p in depthResults: Proliferation, Migration,
DifferentiationImplications
OUTLINE
Transmembrane glycoprotein
Developing and mature brain
Cleaved by enzymes to release amyloid beta
This study: APP and microRNA
AMYLOID PRECURSOR PROTEIN (APP)
Defi ne microRNA Regulates genes to promote neurogenesis
Regulates: 1. migration of neurons2. Neurogenesis/
diff erentiation from a neural progenitor cell (NPC)
Defi ning NPC: biological cell that tends to diff erentiate into a specifi c type of cell
MICRO RNA (miRNA)
How APP regulates microRNAHow microRNA regulates proliferation,
migration, and differentiation
APP deficiency enhances neurogenesis…“but the mechanisms underlying this process are not known.” (citation) Proves relationship, not mechanism
Absence or presence of APP
PURPOSE
Microarray: looks for what APP is regulating
Found that several different microRNAs are regulated
The miRNA that was the most upregulated miR-574-5p
WHY miR-574-5P?
APP negatively regulates miRNA in the cortex and the neural progenitors
APP to 0 miRNA-574-5p
Abnormal clumping of APP product in the brain
*Increase in APP≠AD
APP AND miRNA
A. APP KO = 574 upregulated B. Overexpression of APP = reduced 574 expressionC. Overexpression of APP in APP-KO NPCs decreases the upregulated 574 transcriptsD. Expression of 574 or anti-574 DID NOT aff ect the APP protein level (downstream target)
APP AND miRNA
Function via base pairing with complementary sequences of mRNA molecules
gene silencing via translational repression or targeted degradation
Essential for brain morphogenesis and neurogenesis
The specifics of miRNA-574-5p
Proliferation MigrationDiff erentiationAll three have to be tightly coordinatedessential for the proper development of the nervous
system
BREAKDOWN
APP
miRNA
neurogenesis, differentiation, and migration
proliferation
neural progenitor pool
NPC’s specializing
neurons are born
A STEP FURTHER
Pathogenesis of ADDeveloping and adult brainAblation of APP in mice enhance neural
progenitor cells differentiation during embryonic development
Discovery: APP controls growth and maturation of brain cells
APP may control the balance between proliferation and differentiation of NPCs through the regulation of specific miRNAs
RESULTS
microRNA APP increases proliferationWhen DNA synthesizes creates nucleotides
When neural progenitor cells are transfected with the miR-574-5p, there is 40% reduction in BrdU incorporation
PROLIFERATION
Migration of the NPCs
Subventricular zone (start) = where neurons develop
Cortical cortex (finish) = where neurons end up
MIGRATION
MIGRATION
1. miR-574-4p expression was knocked down in SVZ progenitor cells through electroporation.
2. Traced the migration process.
3. One day after: 62% of the transfected cells present in the SVZ
4. Normal migration: cells primarily distributed throughout CP, with limited number left in SVZ
5. miR-574-4p knockdown cells display a defect in ability to migrate into the CP
APP miRNA differentiation
Neurogenesis and Differentiation
NPCs from APP-knockout mice: 40-50% increase in neurogenesis compared with wild type
NPCs from miRNA-574-5p knockdown: 59% reduction in cells entering the CP
DIFFERENTIATION
miR-574-5p maintains the balance between NPCs
proliferation and differentiation in vitroregulates neuronal cell migration during
cortical development
CONCLUSION
New therapeutic drugsNew biomarkersPotentially use the 574 as a biomarker miR-574-5p = important molecule that
regulates multiple phases of neurogenesis in embryonic cortex and
APP-mediated effects on neural stem cell fate
IMPLICATIONS (LAST SLIDE)
Zhang, W., Thevapriya, S., Kim, P.J., Yu, W.P., Je, H.S., Tan, E.K., Zeng, L.. (2014). Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex. Nature Communications, 5 3330. Retrieved from http://www.nature.com/ncomms/2014/140303/ncomms4330/full/ncomms4330.html#/discussion
“APP is your friend and your enemy.”
“It’s like wheat in the winter. You want a good amount.”
CITATIONS