Loss of aPKCλ in Differentiated Neurons Disrupts the Polarity Complex but Does Not Induce Obvious Neuronal Loss or Disorientation in Mouse Brains

Abstract

Cell polarity plays a critical role in neuronal differentiation during development of the central nervous system (CNS). Recent studies have established the significance of atypical protein kinase C (aPKC) and its interacting partners, which include PAR-3, PAR-6 and Lgl, in regulating cell polarization during neuronal differentiation. However, their roles in neuronal maintenance after CNS development remain unclear. Here we performed conditional deletion of aPKCλ, a major aPKC isoform in the brain, in differentiated neurons of mice by camk2a-cre or synapsinI-cre mediated gene targeting. We found significant reduction of aPKCλ and total aPKCs in the adult mouse brains. The aPKCλ deletion also reduced PAR-6β, possibly by its destabilization, whereas expression of other related proteins such as PAR-3 and Lgl-1 was unaffected. Biochemical analyses suggested that a significant fraction of aPKCλ formed a protein complex with PAR-6β and Lgl-1 in the brain lysates, which was disrupted by the aPKCλ deletion. Notably, the aPKCλ deletion mice did not show apparent cell loss/degeneration in the brain. In addition, neuronal orientation/distribution seemed to be unaffected. Thus, despite the polarity complex disruption, neuronal deletion of aPKCλ does not induce obvious cell loss or disorientation in mouse brains after cell differentiation.

Inhibition of glioblastoma malignancy by Lgl1

“…Lgl1 inactivation is due to phosphorylation by PKCι, which is activated by PTEN loss. Our findings, along with recent data showing a lack of toxicity for neuron-specific PKCι knockouts in mice [ 24 ], support further study of PKCι as a therapeutic target for glioblastoma.…”

NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization

“…By using RNZ reporter mice that express LacZ in nuclei through cre-mediated recombination 17,18 , we confirmed specific recombination by the camk2a-cre transgene in the forebrain region, especially in the cortex and hippocampus (Fig. 1d) 19 . Through several rounds of crossing, we obtained two NF-YA conditional deletion mice: NF-YA flox/flox; cre and flox/ À ; cre mice (see Methods for detail).…”

PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility

“…We therefore restricted our studies to adult BrPerk KO mice at least 3 months old. Previously it has been reported that Cre recombinase is expressed in both cortex and hippocampus in the αCaMKII-Cre strain [ 31 , 32 ]. Western blot analysis of homogenates of different brain regions confirmed that the expression of PERK was substantially knocked down in the prefrontal cortex ( Fig 1A ), which is the major brain region involved in working memory and memory flexibility in rodents [ 1 , 33 ].…”