T-catenin in restricted brain cell types and its potential connection to autism

Background Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin ([alpha]T-cat, CTNNA3) with the development of autism. Where [alpha]T-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown. Methods We used the [alpha]T-cat knockout mouse to examine the localization of [alpha]T-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss. Results We found that [alpha]T-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of [alpha]E-cat expression. Notably, [alpha]T-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While [alpha]T-cat was not detected in neurons of the cerebral cortex, it was abundantly detected within neuronal structures of the molecular layer of the cerebellum. Although [alpha]T-cat loss led to no overt differences in cerebral or cerebellar structure, RNA-sequencing analysis from wild type versus knockout cerebella identified a number of disease-relevant signaling pathways associated with [alpha]T-cat loss, such as GABA-A receptor activation. Conclusions These findings raise the possibility that the genetic associations between [alpha]T-cat and autism may be due to ependymal and cerebellar defects, and highlight the potential importance of a seemingly redundant adherens junction component to a neurological disorder. Keywords: Alpha-T-catenin, Adherens junction, Autism, Alzheimer's disease, Cerebellum, Choroid plexus, Ependyma, Schizophrenia