Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.Key words: schizophrenia; autism; cytokine; poly(I:C); maternal immune activation; IL-6; influenza IntroductionBirth in winter or spring months is an accepted risk factor for schizophrenia, and the preponderance of evidence suggests that the prevalence of influenza in winter months is responsible (Tochigi et al., 2004). Over 25 studies have analyzed schizophrenia incidence after influenza epidemics, and the majority have found an increased incidence among exposed offspring. More recently, Brown and colleagues (Brown and Susser, 2002;Brown et al., 2004;Brown, 2006) examined the medical records of Ͼ12,000 pregnant women and found that second-trimester respiratory infection increases the risk for schizophrenia in the offspring threefold to sevenfold. Because of the high prevalence of influenza infection, they estimate that 14 -21% of schizophrenia cases are caused by maternal infection. These findings are also supported by an association between elevated cytokines or antiinfluenza antibodies in maternal serum and schizophrenia in the offspring (Brown et al., 2004). Maternal infection may also play a role in the pathogenesis of autism (Patterson, 2002). These links are even more remarkable considering that the epidemiological studies are unable to screen for susceptibility genotype. Because of the strong genetic component in autism and schizophrenia, it is likely that only genetically susceptible individuals who were exposed to maternal infection would develop the disorder, suggesting that the risk associated with maternal infect...

Autism is a severe disorder that involves both genetic and environmental factors. Expression profiling of the superior temporal gyrus of six autistic subjects and matched controls revealed increased transcript levels of many immune system related genes. We also noticed changes in transcripts related to cell communication, differentiation, cell cycle regulation and chaperone systems. Critical expression changes were confirmed by qPCR (BCL6, CHI3L1, CYR61, IFI16, IFITM3, MAP2K3, PTDSR, RFX4, SPP1, RELN, NOTCH2, RIT1, SFN, GADD45B, HSPA6, HSPB8 and SERPINH1). Overall, these expression patterns appear to be more associated with the late recovery phase of autoimmune brain disorders, than with the innate immune response characteristic of neurodegenerative diseases. Moreover, a variance-based analysis revealed much greater transcript variability in brains from autistic subjects compared to the control group, suggesting that these genes may represent autism susceptibility genes and should be assessed in follow-up genetic studies.

Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.

In vivo studies have previously shown that Saccharomyces cerevisiae ribosomal protein (RP) gene expression is controlled by the transcription factor repressor activator protein 1 (Rap1p) in a TFIID-dependent fashion. Here we have tested the hypothesis that yeast TFIID serves as a coactivator for RP gene transcription by directly interacting with Rap1p. We have found that purified recombinant Rap1p specifically interacts with purified TFIID in pull-down assays, and we have mapped the domains of Rap1p and subunits of TFIID responsible. In vitro transcription of a UAS RAP1 enhancer-driven reporter gene requires both Rap1p and TFIID and is independent of the Fhl1p-Ifh1p coregulator. UAS RAP1 enhancer-driven transactivation in extracts depleted of both Rap1p and TFIID is efficiently rescued by addition of physiological amounts of these two purified factors but not TATA-binding protein. We conclude that Rap1p and TFIID directly interact and that this interaction contributes importantly to RP gene transcription.Eukaryotic mRNA gene transcription is controlled by the action of modular enhancer-binding transactivators, proteins composed of separable DNA binding domains (DBD) and activation domains (AD). DNA-bound transactivators functionally interact with the mRNA gene transcription machinery, the so-called general transcription factors (GTFs) TFIIA, -B, -D, -E, -F, and -H plus RNA polymerase II (RNAP II), to stimulate formation and/or function of the RNAP II preinitiation complex (PIC) (67). Activators also collaborate with one or more factors termed coactivators, proteins that serve as receptors for the transfactor-AD activation signal. Coactivators link transactivator-enhancer DNA binding to the PIC (43) and can be divided into several classes: those that are chromatin active, the mediator complex, and the individual components of the mRNA gene transcription machinery itself.One of the first and likely rate-limiting steps in mRNA gene transcription is the binding of TFIID to the promoter (36,40,47). TFIID is a multisubunit assembly composed of 15 evolutionarily conserved (86) subunits, the TATA-binding protein (TBP) and 14 TBP-associated factors (TAFs) (72). This GTF displays high-affinity, sequence-specific promoter DNA binding activity. Two classes of yeast mRNA-encoding genes have been defined with respect to TFIID TAF function; the first, which is TAF dependent (TAF dep ), requires TAF function for transcription, while the second and smaller group is TAF independent (TAF ind ) (29,31,45,58,81,92). Both types of genes require TBP for wild-type (WT) levels of transcription, but in the case of the TAF ind genes, TBP appears to be recruited via mechanisms distinct from TFIID (4, 80).When mRNA-encoding genes are monitored for TBP and TAF occupancy by chromatin immunoprecipitation (ChIP) assay, TAF dep genes exhibit higher TAF/TBP occupancy ratios than TAF ind genes (39, 45). Three models for TAF function have been proposed (22, 23): TAFs mediate core promoter recognition; TAFs provide essential catalytic activities tha...

We previously defined Saccharomyces cerevisiae TFIID as a 15-subunit complex comprised of the TATA binding protein (TBP) and 14 distinct TBP-associated factors (TAFs). In this report we give a detailed biochemical characterization of this general transcription factor. We have shown that yeast TFIID efficiently mediates both basal and activator-dependent transcription in vitro and displays TATA box binding activity that is functionally distinct from that of TBP. Analyses of the stoichiometry of TFIID subunits indicated that several TAFs are present at more than 1 copy per TFIID complex. This conclusion was further supported by coimmunoprecipitation experiments with a systematic family of (pseudo)diploid yeast strains that expressed epitope-tagged and untagged alleles of the genes encoding TFIID subunits. Based on these data, we calculated a native molecular mass for monomeric TFIID. Purified TFIID behaved in a fashion consistent with this calculated molecular mass in both gel filtration and rate-zonal sedimentation experiments. Quite surprisingly, although the TAF subunits of TFIID cofractionated as a single complex, TBP did not comigrate with the TAFs during either gel filtration chromatography or rate-zonal sedimentation, suggesting that TBP has the ability to dynamically associate with the TFIID TAFs. The results of direct biochemical exchange experiments confirmed this hypothesis. Together, our results represent a concise molecular characterization of the general transcription factor TFIID from S. cerevisiae.The general transcription factor TFIID plays a central role in the initiation of mRNA gene transcription. TFIID is the only general transcription factor with specific TATA box binding activity, and the expression of many RNA polymerase IItranscribed genes is dependent on TFIID function (1, 26). Saccharomyces cerevisiae TFIID is composed of 15 subunits, TATA binding protein (TBP) and 14 distinct TBP-associated factors (TAFs) (61). The TBP subunit is responsible for the TATA box binding activity of TFIID, and TBP sequence and structure are both highly conserved throughout eukaryotic species. Like TBP, the TAF subunits of TFIID have also been highly conserved during eukaryotic evolution (6,22,66), and in aggregate, TAFs appear to serve multiple functions within the TFIID holocomplex. Early models, based on in vitro studies with individual recombinant subunits or subcomplexes of TFIID subunits, argued that TAFs functioned either as core promoter selectivity factors or as general coactivators, integrating signals between gene-specific trans-activating factors and the general transcription machinery (1). Although initially questioned, recent in vivo studies with S. cerevisiae and metazoans support both the coactivator and core promoter functions of TAFs within TFIID (1, 42, 59).Studies with numerous eukaryotic systems have yielded invaluable insights into the role of TFIID in the regulation of mRNA gene transcription. However, despite this large body of information regarding its functional properties, many fund...