Functional roles of neural aPKCs in mouse brain development and survival

Abstract

Conserved protein complexes establish and maintain cell polarity. In turn, cell polarity is indispensable for fundamental developmental processes such as asymmetric division of stem cells and establishment of subcellular membrane polarization during cell differentiation. There are three well characterized polarity complexes. Atypical Protein Kinase C (aPKC) is a conserved constituent of the PAR complex that phosphorylates not only substrates within this complex, but also in the other polarity complexes. Outside of the polarity complex, aPKC regulates a myriad of cellular processes such as migration, metabolism, and survival. In mammals, two paralogs, Prkci and Prkcz, form the aPKC subfamily. Here, we characterized the expression of the Prkci and Prkcz paralogs, including a variant transcript of Prkcz, in the mouse brain and specific cells of the neural lineage. We generated a series of mice with individual and collective ablation of the two aPKC paralogs in neural stem cells, new-born neurons, astrocytes and NG2+ cells, as well as a mouse expressing kinase-inactive PRKCI in neural progenitors. We examine the effects of loss of aPKC paralogs or its kinase activity on gross brain development and organismal viability. Our results identify a critical window in neural progenitor differentiation wherein aPKC function is indispensable for neurodevelopment. Beyond this period, the ablation of even both aPKCs is characterized by a conspicuous absence of anticipated drastic effects. The genetic models developed might prove useful for further interrogating aPKC function in neurodevelopment and neuronal function or to reveal the role of polarity complex function in neurons, astrocytes and oligodendrocytes during stress, injuries or diseases.