title: DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.
abstract: Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/β-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/β-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/β-catenin pathway.
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: P-M
authors.initials: PM
authors.lastname: Martin
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.|TETRAD Graduate Program, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Stanley
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Ross
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Freitas
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Moyer
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.|Division of Child Neurology, Department of Neurology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Brumback
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Iafrati
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Stapornwongkul
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dominguez
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kivimäe
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Mulligan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pirooznia
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Woodbury, NY, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: McCombie
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Potash
authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Zandi
authors.affiliation: Institute for Genomics and Multiscale Biology, Department of Psychiatry and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.|UCSF Weill Institute for Neurosciences, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.|UCSF Weill Institute for Neurosciences, University of California San Francisco (UCSF), San Francisco, CA, USA.|Kavli Institute for Fundamental Neuroscience, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Sohal
authors.affiliation: Department of Psychiatry, University of California San Francisco (UCSF), San Francisco, CA, USA.|TETRAD Graduate Program, University of California San Francisco (UCSF), San Francisco, CA, USA.|UCSF Weill Institute for Neurosciences, University of California San Francisco (UCSF), San Francisco, CA, USA.|Kavli Institute for Fundamental Neuroscience, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: B N R
authors.initials: BNR
authors.lastname: Cheyette
mesh_terms: D000818:Animals; D001007:Anxiety; D001008:Anxiety Disorders; D049229:Dendritic Spines / Q000235:genetics* / Q000378:metabolism; D003863:Depression; D003866:Depressive Disorder; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D001523:Mental Disorders / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017966:Pyramidal Cells / Q000502:physiology; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C509983:Dixdc1 protein, mouse; D050491:Glutamate Plasma Membrane Transport Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3