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A latent neurogenic program in astrocytes regulated by Notch signaling Magnusson JP, Göritz C,...
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Transcript of A latent neurogenic program in astrocytes regulated by Notch signaling Magnusson JP, Göritz C,...
A latent neurogenic program in astrocytes regulated by Notch signalingMagnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EM,Lindvall O, Kokaia Z, Frisén J.
Science. 2014 Oct 10;346(6206):237-41. doi: 10.1126/science.346.6206.237.
Jitesh Doshi [670302401]CS502 Computational BiologyUniversity of Illinois at Chicago
What we’re going to look at?
Overview of Neurogenesis and Notch signaling
Goal of the presented work Approach Results Conclusions Questions I thought could be relevant If you have any questions References
BRAIN
NEURON
ASTROCYTES
NOTCH SIG.
A highly complex organ specialized in reasoning and logic imparting cognitive abilities and senses
A center of all actions we perform originative or as a response to stimuli
Predominantly composed of neuronal sense as a means of transport of signal
STRIATUM
BRAIN
NEURON
ASTROCYTES
NOTCH SIG.
An electrically excitable cell which can process and transmit information
Also help in memory development
Do not divide further (G0 phase)
* Fundamental principle of Neural Networks
STRIATUM
BRAIN
NEURON
ASTROCYTES
NOTCH SIG.
Star shaped cells
Helps in metabolism, migration, response to injuries and many more functions
Dysfunction may cause aberrant neuronal circuitry
Thus involved in neurodevelopmental disorders
STRIATUM
BRAIN
NEURON
ASTROCYTES
NOTCH SIG.
Evolutionary conserved signaling pathway
Regulates cell-fate determination during development
Maintains adult tissue homeostasis
Regulates neurogenesis
STRIATUM
BRAIN
NEURON
ASTROCYTES
NOTCH SIG.
STRIATUM
Subcortical part of fore-brain
Involved in movement and motivation
And some other cognitive functions
Not known to have neurogenic abilities
Neurogenesis
Generation of neurons Very active and occurs widely during infant
stages Restricted in adult brains to some parts of
the brain Neither exchanged or replaced in
pathological conditions Play a very important role in learning and
memory Associated with many diseases
Aim of the study
To explore in vivo neurogenic potential of astrocytes A long-held scientific theory says that the
nervous system is fixed and incapable of regeneration
Recent research have shown that neurogenesis is present in some parts of the brain
This study throws light on neurogenesis in astrocytes
Approach
Induced neurogenesis in a transgenic mice (Connexin-30-CreER) with a reporter protein (YFP)
Specific recombination using tamoxifen Analysis by identifying biomarkers Validation by cross-replication of
experiments
Methodology
Injection of Tamoxifen Activates Cx-30-CreER
Allows specific recombination in astrocytes and sub ventricular zone
Induction of stroke using transient occlusion of middle cerebral artery causing ischemic lesions
Stroke triggered doublecortin positive (DCX+) recombined cells
After two weeks, astrocytes expressed Ascl1, a pro-neural transcription factor
Results
Results
Results
Recombined cells stopped expressing S100, which is an astrocyte marker
Two weeks – tightly packed clusters of recombined cells
Neuron formation and new synaptic junctions were observed
Validations
Possibility of sub ventricular region being origin of neurogenesis was excluded using local recombination by injecting adenovirus in striatum
Uninjured cells did not show any marker to suggest neurogenesis
Surprisingly, Notch signaling pathway was seen to be significantly downregulated in injured mice
Suggesting that Notch signaling regulates the neurogenesis in astrocytes
Markers for Notch signaling were undetectable at the end of the treatment
Artificial continuation of Notch signaling after stroke – No neurogenesis
Artificial reduction of Notch signaling in absence of stroke - Neurogenesis
Conclusion
Astrocytes do have a neurogenic program encoded in their genome, which requires specific activation
This revelation is very important in treatment of neuro-degenerative diseases like Parkinson’s disease
It ensures an alternative strategy of indigenous neurogenesis than interneuron transplantation
Questions to be asked
Are there any other activators/regulators of such a neurogenic pathway?
Could the neurogenesis in astrocytes be precisely modeled using statistical / computational techniques to perfect the neuron replacement strategies?
Will it have any undesirable consequences at the psychological level in a patient undergoing such treatment?
An interesting extension
Somewhat parallel work going on in Univ. of New Mexico, added a great value to this work
They present two computational models of neurogenesis to investigate possible functional implications One, a spiking, biologically realistic model
Basic growing feedforward model
Could result in an interesting anticipated outcome: Improvement of decision making in no-prior-experience situations
Adult Neurogenesis: implications on Human and Computational Decision making
Any questions, in case?
References
Aimone JB et al, Eur J Neurosci. 2011 Mar;33(6):1160-9. doi: 10.1111/j.1460-9568.2011.07615.x.
Becker S, Hippocampus. 2005;15(6):722-38. Cunio et al Scientific Reports 2, Article number: 735 doi:10.1038/srep00735
Vineyard et al, Lecture Notes in Computer Science Volume 8027, 2013, pp 531-540