Negative regulators of neuronal polarity means the molecules will inhibit other downstream or upstream molecules which are involved in controlling the Cytoskeleton formation, stability, endocytosis etc.
PTEN (Phosphatase and tensin homolog)
It is a lipid phosphatase protein which counteracts the enzyme PI3 K (PI3 kinase) by converting PIP3 formed by PI3K into PIP2. Overexpression of this molecule will lead to prevention of PAR 3 localization to neurites and inhibits axon formation. If the PTEN expression is downregulated using SiRNA, then all the neurites becomes axons and there will reduction in dendrite formation. From this we can conclude that PTEN is important for the growth specific single axon. PAR 3 (Drosophila epithelia and neuroblasts) actually directly interacts with PTEN and this property leads to negative feedback loop. Where the PI3Kinase will recruit PAR 3 which in turn brings the PTEN molecule, thus leading to maintenance of PIP3 concentration in axon or PIP2 formed will bind to actin associated proteins such as WASP and regulate the actin formation.
PTEN is associated with PI3K and GSK3β; GSK3β inhibits PTEN by Phosphorylating at its C terminus. Until GSK3β is active, the PTEN activity is downregulated and therefore upregulation of PTEN happens by GSK3β inhibition which might provide a negative feedback regulation by again counteracting at PI3K activity.
Rho A (Rho GTPase Family)
Rho A is a Rho GTPase family protein which has the negative regulation role in the axon stability. Rho A negatively regulates the neurite outgrowth and modulating its signaling pathway will lead to axon regeneration in the central nervous system during injury. ROCK which is a Rho kinase effector accompanies Rho A in regulating axon growth and actin dynamics during neuritogenesis of cultured cerebellar granule neurons. Rho A-ROCK pathway with profilin II regulates actin and microtubule stability. Still Rho A knock mice is not created inorder to analysis the function of Rho A in neuronal polarity.
GSK3β (Glycogen synthase kinase 3β)
GSK3β is negative regulator of CRMP -2 (collapsin regulated mediator protein-2) which is GSK3β substrate responsible for microtubule polymerization. GSK3β is regulated by Akt protein which is activated by the PIP3 produced by PI3 Kinase. The protein not involved in establishment of neuronal polarity, but also plays a vital role in maintenance of neuronal polarity. CRMP-2 will be phosphorylated at thr-514 by GSK3β thereby making it unable to bind with tubulin dimer and NUMB. Overexpression of active GSK3β will lead to prevention of axon formation, whereas in inactive form it will lead to multiple axon formation. It also inactivates the MAP (microtubule associated proteins) protein by Phosphorylating MAP1B and APC (adenomatous polyposis coil).
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