Competing molecular interactions of aPKC isoforms regulate neuronal polarity

Atypical protein kinase C (aPKC) isoforms zeta and lambda interact with polarity complex protein Par3 and are evolutionarily conserved regulators of cell polarity. Prkcz encodes aPKC-zeta and PKM-zeta, a truncated, neuron-specific alternative transcript, and Prkcl encodes aPKC-lambda. Here we show that, in embryonic hippocampal neurons, two aPKC isoforms, aPKC-lambda and PKM-zeta, are expressed. The localization of these isoforms is spatially distinct in a polarized neuron. aPKC-lambda, as well as Par3, localizes at the presumptive axon, whereas PKM-zeta and Par3 are distributed at non-axon-forming neurites. PKM-zeta competes with aPKC-lambda for binding to Par3 and disrupts the aPKC-lambda-Par3 complex. Silencing of PKM-zeta or overexpression of aPKC-lambda in hippocampal neurons alters neuronal polarity, resulting in neurons with supernumerary axons. In contrast, the overexpression of PKM-zeta prevents axon specification. Our studies suggest a molecular model wherein mutually antagonistic intermolecular competition between aPKC isoforms directs the establishment of neuronal polarity.