@article{b9a4db621f7c46c4bbaeafa102f5d9a0,
title = "αT-catenin in restricted brain cell types and its potential connection to autism",
abstract = "Background: Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin (αT-cat, CTNNA3) with the development of autism. Where αT-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown. Methods: We used the αT-cat knockout mouse to examine the localization of αT-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss. Results: We found that αT-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of aE-cat expression. Notably, αT-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While αT-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 αT-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 αT-cat loss, such as GABA-A receptor activation. Conclusions: These findings raise the possibility that the genetic associations between αT-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 = "Adherens junction, Alpha-T-catenin, Alzheimer's disease, Autism, Cerebellum, Choroid plexus, Ependyma, Schizophrenia",
author = "Folmsbee, {Stephen Sai} and Wilcox, {Douglas R.} and Koen Tyberghein and {De Bleser}, Pieter and Tourtellotte, {Warren G.} and Hengel, {Jolanda van} and {van Roy}, Frans and Gottardi, {Cara J.}",
note = "Funding Information: Mice were anesthetized and subjected to intracardiac perfusion with saline, followed by perfusion of 4 % paraformaldehyde fixative. Whole brains were removed and post-fixed in 4 % formaldehyde and embedded in paraffin blocks. For immunofluorescence, tissue sections were deparaffinized and antigens were retrieved by boiling in citrate buffer for 30 min. Fluorescent images were captured using a Zeiss Axioplan epifluorescence microscope. Primary antibodies used were: BD Biosciences mouse anti-α-E-catenin (#610193), rabbit anti-α-T-catenin (polyclonal #952) [11], rat anti-α-T-catenin (monoclonal, 115 9_12A4S4), Millipore mouse anti-α-T-catenin (MAB20 87), BD Transduction Laboratories mouse anti-E-cadherin (610182), BD Transduction Laboratories mouse anti-N-cadherin (#610920), Santa Cruz Biotechnology rabbit anti-β-catenin (H-102, SC-7199), Millipore rabbit anti-Connexin-43 (AB1728), Santa Cruz Biotechnology rabbit anti-p120-catenin (S-19, SC-1101), Santa Cruz Biotechnology goat anti-δ-catenin (C-20, SC-16512), Invitrogen mouse anti-ZO-1 (33-9100), Synaptic Systems rabbit anti GABRA2 (224-103), Santa Cruz Biotechnology goat anti-doublecortin (C-18, SC-8066), Dako rabbit anti-GFAP (Z0334), Leica Biosystems rabbit anti-Ki-67 (NCL-Ki67p), Sigma mouse anti-Tuj1 (T8660), Swant rabbit anti-Calbindin D28K (CB-38). Secondary antibodies used were: Alexa Fluor 488/568 goat anti-mouse/rabbit (Life Technologies) and Alexa Fluor 568 donkey anti-goat (Life Technologies). Tissue processing was supported by the Northwestern University Mouse Histology and Phenotyping Laboratory (MHPL) and a Cancer Center Support Grant (NCI CA060553). H&E histology was performed by the MHPL. Funding Information: S.S.F. is supported by the National Institutes of Health (T32GM008152, T32CA09560, F30 ES024622) and the American Heart Association pre-doctoral fellowship (15PRE21850010). D.R.W. is supported by the National Institutes of Health (T32GM008152). W.G.T. is supported by the National Institutes of Health (NS089626, OD010945 and CA060553). F.v.R.. J.v.H, P.d.B., and K.T. are supported by the Research Foundation - Flanders (FWO) and the Belgian Science Policy (Interuniversity Attraction Poles – IAP7/07). C.J.G. is supported by the National Institutes of Health (GM076561) and Northwestern University bridge funds. Funding Information: We thank the MHPL and Human Pathology Core Facilities of Northwestern, as well as Dr. Richard Miller for his aid in providing the instruments for the fixation and perfusion of mouse brains. We also thank Jack Kessler and his laboratory, particularly Sarah Brooker, as well as Anjen Chenn (University of Illinois, Chicago), for discussions. S.S.F. is supported by the National Institutes of Health (T32GM008152, T32CA09560, F30 ES024622) and the American Heart Association pre-doctoral fellowship (15PRE21850010). D.R.W. is supported by the National Institutes of Health (T32GM008152). W.G.T. is supported by the National Institutes of Health (NS089626, OD010945 and CA060553). F.v. R. J.v. H, P.d. B., and K.T. are supported by the Research Foundation-Flanders (FWO) and the Belgian Science Policy (Interuniversity Attraction Poles-IAP7/07). C.J.G. is supported by the National Institutes of Health (GM076561) and Northwestern University bridge funds. Publisher Copyright: {\textcopyright} 2016 The Author(s).",
year = "2016",
doi = "10.1186/s40303-016-0017-9",
language = "English (US)",
volume = "4",
journal = "Journal of Molecular Psychiatry",
issn = "2049-9256",
publisher = "BioMed Central Ltd.",
number = "1",
}