1. Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, 10043 Orbassano, Torino, Italy
2. Department of Human Genetics, Catholic University of Leuven and Flanders Interuniversity Institute of Biotechnology, 3000 Leuven, Belgium
3. *These authors contributed equally to this work

Correspondence to: Fabian Feiguin¹Carlos G. Dotti^1,2 Correspondence and requests for materials should be addressed to F.F. (Email: fabian.feiguin@unito.it) or C.G.D. (Email: carlos.dotti@unito.it).

Neuronal polarization occurs shortly after mitosis. In neurons differentiating in vitro, axon formation follows the segregation of growth-promoting activities to only one of the multiple neurites that form after mitosis^{1, 2}. It is unresolved whether such spatial restriction makes use of an intrinsic program, like during C. elegans embryo polarization³, or is extrinsic and cue-mediated, as in migratory cells⁴. Here we show that in hippocampal neurons in vitro, the axon consistently arises from the neurite that develops first after mitosis. Centrosomes, the Golgi apparatus and endosomes cluster together close to the area where the first neurite will form, which is in turn opposite from the plane of the last mitotic division. We show that the polarized activities of these organelles are necessary and sufficient for neuronal polarization: (1) polarized microtubule polymerization and membrane transport precedes first neurite formation, (2) neurons with more than one centrosome sprout more than one axon and (3) suppression of centrosome-mediated functions precludes polarization. We conclude that asymmetric centrosome-mediated dynamics in the early post-mitotic stage instruct neuronal polarity, implying that pre-mitotic mechanisms with a role in division orientation may in turn participate in this event.

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