DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/beta-catenin signaling

Martin, P. M., Stanley, R. E., Ross, A. P., Freitas, A. E., Moyer, C. E., Brumback, A. C., Iafrati, J., Stapornwongkul, K. S., Dominguez, S., Kivimae, S., Mulligan, K. A., Pirooznia, M., McCombie, W. R., Potash, J. B., Zandi, P. P., Purcell, S. M., Sanders, S. J., Zuo, Y., Sohal, V. S., Cheyette, B. N. (February 2018) DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/beta-catenin signaling. Mol Psychiatry, 23 (2). pp. 467-475. ISSN 1476-5578 (Electronic)1359-4184 (Linking)

Abstract

Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/beta-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/beta-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/beta-catenin pathway.Molecular Psychiatry advance online publication, 18 October 2016; doi:10.1038/mp.2016.184.

Item Type:	Paper
Subjects:	diseases & disorders > mental disorders diseases & disorders > mental disorders > personality disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > catenins organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dendritic cells > dendritic spines organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dendritic cells > dendritic spines organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dendritic cells > dendritic spines bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > single nucleotide polymorphism organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > synapse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Wnt
CSHL Authors:	McCombie, W. Richard
Communities:	CSHL labs > McCombie lab
Depositing User:	Matt Covey
Date:	February 2018
Date Deposited:	27 Oct 2016 15:44
Last Modified:	07 Mar 2018 16:23
PMCID:	PMC5395363
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/33819

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