RESUMO
Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/ß-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/ß-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/ß-catenin pathway.
Assuntos
Espinhas Dendríticas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Animais , Ansiedade , Transtornos de Ansiedade , Espinhas Dendríticas/metabolismo , Depressão , Transtorno Depressivo , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Transtornos Mentais/genética , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Células Piramidais/fisiologia , Comportamento Social , Sinapses/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismoRESUMO
The bovine papillomavirus E2 protein is a multifunctional protein that activates viral transcription, co-operates in initiation of viral DNA replication, and is required for long-term episomal maintenance of viral genomes. The EBNA1 protein of Epstein-Barr virus is required for synthesis and maintenance of Epstein-Barr virus genomes. Both viral proteins act through direct interactions with their respective DNA sequences in their origins of replication. The chimeric protein E2:EBNA1, which consists of an transactivation domain of E2 and DNA binding domain of EBNA1 supported the replication of the chimeric origin that contained EBNA1 binding sites in place of the E2 binding sites principally as full-length E2 did in the case of papillomavirus minimal origin. This indicates that the chimeric protein E2:EBNA1 is competent to assemble a replication complex similar to the E2 protein. These data confirm the earlier observations that the only part of E2 specifically required for its activity in replication is the N-terminal activation domain and the function of the DNA binding domain of E2 in the initiation of replication is to tether the transactivation domain of E2 to the origin of replication.
Assuntos
Papillomavirus Bovino 1/genética , Replicação do DNA , DNA Viral/fisiologia , Herpesvirus Humano 4/genética , Sítios de Ligação , Papillomavirus Bovino 1/química , Papillomavirus Bovino 1/metabolismo , Proteínas de Ligação a DNA/fisiologia , Antígenos Nucleares do Vírus Epstein-Barr/fisiologia , Herpesvirus Humano 4/química , Herpesvirus Humano 4/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/fisiologia , Origem de Replicação , Transativadores/fisiologia , Proteínas Virais/fisiologiaRESUMO
Disrupted-in-Schizophrenia-1 (DISC1) is a genetic susceptibility locus for major mental illness, including schizophrenia and depression. The Disc1 protein was recently shown to interact with the Wnt signaling protein, DIX domain containing 1 (Dixdc1). Both proteins participate in neural progenitor proliferation dependent on Wnt signaling, and in neural migration independently of Wnt signaling. Interestingly, their effect on neural progenitor proliferation is additive. By analogy to Disc1, mutations in Dixdc1 may lead to abnormal behavior in mice, and to schizophrenia or depression in humans. To explore this hypothesis further, we generated mice mutant at the Dixdc1 locus and analyzed their behavior. Dixdc1(-/-) mice had normal prepulse inhibition, but displayed decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity. Our results suggest that Dixdc1(-/-) mice will be a useful tool to elucidate molecular pathophysiology involving Disc1 in major mental illnesses.