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F. Calderon de AndaPolarity before polarization

Abstract :

Among the cell populations that form the nervous system, neurons are excellent examples of cells that can propagate signals efficiently. The shape of a neuron supplies valuable clues to its function, typically extending a single long thin axon, which will transmit signals, and several shorter and thicker dendrites, which receive them. These domains are established early as neurons differentiate and extend processes and maintained over a life span that can last decades. For many years it has been studied how these domains are form and maintain to create the neuronal polarization. This process is best studied in dissociated hippocampal neurons in vitro. When these neurons are dissociated from the embryonic hippocampus and cultured, they reproducibly establish their polarity, with a single axon and several dendrites.

How neurons acquire a polarized morphology is a fundamental question in developmental neurobiology.

The current view is that axon formation is the first sign of neuronal polarization. However, new data suggest that the centrosome and a polarized cytoplasm not only determines the position of neurite emergence but also set the conditions for morphological polarization. Nonetheless, little is known about the mechanisms of axon specification in vivo and how intracellular and extracellular programs cooperate to define the site of axon elongation.
In the developing mammalian cortex, the first sign of axon outgrowth is evident in neuronal cells with multipolar morphology located in the lower intermediate zone (IZ). The multipolar neuron is a transitional stage occurring after newborn bipolar neurons ascend from the ventricular zone (VZ) to the IZ and before the more mature bipolar neurons migrate out of the IZ and into the cortical plate (CP). It has been reported that radially migrating bipolar neurons ascending from the VZ or migrating out of the IZ have a centrosome oriented towards the CP, whereas axons elongate apically towards the VZ. This observation contradicts the suggestion that centrosome position predicts the site of axon outgrowth.

We have performed functional analysis of centrosome behavior in multipolar neurons during axon formation in situ, using a combination of time-lapse imaging and in utero transfection of embryonic mouse cortex. We found that the apical localization of centrosomes is closely associated with initial outgrowth of the descending axons. Further, we show that the centrosome is necessary for axon formation since centrosome disruption by chromophore-assisted light inactivation (CALI) of the centrosomal protein Centrin2 and down-regulation of the centriolar satellite protein PCM-1 leads to axon formation defects and impaired neuronal migration. Finally, we found that the motility of the centrosome inversely depends on microtubule polymerization. Decreased microtubule stability or down-regulation of the centrosomal protein Cep120 increased centrosome motility and impaired axon formation as well as neuronal migration. In contrast, increased microtubule stability did not affect axon formation but changed the position of axon outgrowth in accordance with the centrosome position. Our results reveal the dynamic nature of the centrosome in multipolar neurons and suggest that such movement is essential for the initial axon formation.

Selected publications

Calderon de Anda F., Pollarolo G., Da Silva J.S., Camoletto P., Feiguin F. and Dotti C.G.
Centrosome localization determines neuronal polarity. Nature. 436 (2005) 704-708.
Calderon de Anda F., Gartner A., Tsai L-H and Dotti C.G.Pyramidal neuron polarity axis is defined at the bipolar stage. J Cell Sci, 121(2008) 178-185.
Calderon de Anda F., Meletis K., Rei D., and Tsai L-H. Centrosome motility is essential for proper axon formation. Submitted