The hippocampal neurons form a spikes and small proturusion veils at stage 1. This is stage where the neuron stem cell breaks out from the cell cycle.
Then the truncated protrusions develop into a several neurites at stage 2.
At stage 3, All the neurites are roughly equal in length, in which only one neurite will start to break the initial morphology symmetry and grows at rapid rate and thus they eshtablish polarity.
The extracellular cues can guide which neurite to grow as axon. The extracellular cues are highly concentrated over the stage 2 immature neurites. Well the guidance happens through the help of downstream signalling molecules present within the neurites. PI 3 kinase and its lipid products such as PIP3 determines and maintains the internal polarity. PI 3 kinase activity is localized at the tip of the newly specificed growing axon and its activated when its get the signal from the extracellular cues.
The Signalling cascades helps the centrosome to position at one of the neurite and these centrosome position is responsible for the growth of a axon, because it guides the microtubules to move in one particular neurite. If a neuron is having multiple centrosomes, then it will lead to formation of multiple axons. From this its well understood that centrosome is indirectly responsible for the axon formation, since its controlled by PI 3 kinase, cdc 42 and other regulatory molecules.
Soon after the axon starts it rapid growth action, the other neurites enlongates and acquire the charactersitics of dendrites which is at stage 4.
Finally the neurons form the synaptic contacts and eshtablish a neuronal network at stage 5.
So at stage 2, There happens to be two kinds of feedback signals which is very balanced. They are positive and negative feedback signals. In this negative regulations, the actin dynamics decrease and microtubule catastrophe occurs, whereas in positive regulation, actin dynamics increases and microtubule assembly occurs. Hence the neurites are found to be of same length and it wont grow unless some extracellular cues triggers the downstream regulating molecules. When balance is broken, then the axon growth occurs, where the postive feedback plays a major role than the negative feedback loop.
PIP3, Akt and GSK 3β signaling cascade determines the fate of the axon growth. When the receptor gets activated or triggered by some extracellular cues like netrins or BDNF, then it’s the Ras, which is a G protein activates the PI-3 kinase. The PI-3 kinase converts the lipid membrane molecule PIP2 to PIP3 which activates the PDK 1 (Phosphoinositide dependent kinase 1). The PDK 1 and other kinases such as integrin linked kinase phosphorylates the kinase Akt protein (PKB) at threonine 308 and serine 473. The phosphorylated Akt protein will inactivate the GSK 3β by Phosphorylation.
GSK 3β will activate the regulator proteins which is will be responsible for the microtubule catastrophe. Hence the activated GSK 3β or overexpression of GSK 3β will not allow the formation of axon, whereas knockout of GSK 3β gene have lead to formation of multiple axon. Therefore, the GSK 3β will be found inactive at the tips of the growing axon or growth cone.
RAP 1B (ras related protein 1B), which is ras superfamily GTPase localize at the tips of the axon before the cdc 42 and PAR complex accumulates. It is said that the accumulation RAP 1 protein in one particular neurite is responsible for the axon specification and recruitment of other proteins for axonal growth. The TrkA A receptor is activated by the extracellular cues, which will consequently recruits the GEFs of RAP 1 and adaptor protein (CRK) and then stimulates the RAP1.
Rho GTPase: Rac 1 and cdc 42 activation will lead to the elongation of the neurite, whereas in the case of Rho A activation will lead to the inhibition of the neurite outgrowth. Certain Rho GTPase effectors also influence in the neurite outgrowth such as P35, PAK, MRCK, N- WASP and IQGAP3. There are regulators of Rac 1: TIAM 1 and STEF (SIF and TIAM 1 like exchange factors), which regulates the upstream molecules of it.
PAR complex: PAR 3 and PAR 6 with aPKC will form a complex with cdc42. The PAR complex will activate the Rac 1 protein through the TIAM 1 and STEF.
This picture shows how the PAR complex gets localized. They are transported from the cell body to the growing axon by the motor protein kinesin 2.
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