Role of TIF1α as a modulator of embryonic transcription in the mouse zygote

The first events of the development of any embryo are under maternal control until the zygotic genome becomes activated. In the mouse embryo, the major wave of transcription activation occurs at the 2-cell stage, but transcription starts already at the zygote (1-cell) stage. Very little is known about the molecules involved in this process. We show that the transcription intermediary factor 1 α (TIF1α) is involved in modulating gene expression during the first wave of transcription activation. At the onset of genome activation, TIF1α translocates from the cytoplasm into the pronuclei to sites of active transcription. These sites are enriched with the chromatin remodelers BRG-1 and SNF2H. When we ablate TIF1α through either RNA interference (RNAi) or microinjection of specific antibodies into zygotes, most of the embryos arrest their development at the 2–4-cell stage transition. The ablation of TIF1α leads to mislocalization of RNA polymerase II and the chromatin remodelers SNF2H and BRG-1. Using a chromatin immunoprecipitation cloning approach, we identify genes that are regulated by TIF1α in the zygote and find that transcription of these genes is misregulated upon TIF1α ablation. We further show that the expression of some of these genes is dependent on SNF2H and that RNAi for SNF2H compromises development, suggesting that TIF1α mediates activation of gene expression in the zygote via SNF2H. These studies indicate that TIF1α is a factor that modulates the expression of a set of genes during the first wave of genome activation in the mouse embryo

How Accurately Can Parents Judge Their Children\u27s Boredom in School?

The purpose of the present study was to explore what parents know about their Children’s boredom in school; specifically, the frequency, intensity, and antecedents of their Children’s boredom, as well as how they cope with boredom. A questionnaire was administered to 437 grade 9 students (54% female, Mage = 14.82) and their parents (72% mothers, 14% fathers, 12% both parents, Mage = 45.26) measuring variables related to students boredom in mathematics class. Three different measurements were used to evaluate the accuracy of parents’ judgments: (1) the correlation between parents’ and students’ answers, (2) the mean differences between parents’ and students’ answers, and (3) the mean values of absolute differences of parents’ and students’ answers. The results suggest that parents generally have an informed knowledge about their child’s boredom and related facets. This is reflected by a mean correlation of medium size (r = 0.34) and a small mean effect size of the difference between parents’ and students’ judgments over all items (d = 0.20). Parents are also substantially better in judging their Children’s boredom compared to guessing for all variables (mean effect size of d = 0.65). They had the most precise judgments for the frequency and intensity of boredom. The antecedents of boredom (e.g., characteristics of instruction) were also well estimated by parents; specifically, parents tend to have a bias in favor for their children evidenced by overestimating antecedents that cannot be influenced by the students and underestimating those that can be influenced by the students. The least concordance was found between parents’ and Children’s perception of boredom coping strategies (e.g., accepting boredom), implying that parents lack information about how their children intentionally cope with boredom. Implications for research on student boredom are discussed as well as practical applications involving parents in boredom prevention

Euthymic Patients with Bipolar Disorder Show Decreased Reward Learning in a Probabilistic Reward Task

Background: Bipolar disorder (BPD) features cycling mood states ranging from depression to mania with intermittent phases of euthymia. Bipolar disorder subjects often show excessive goal-directed and pleasure-seeking behavior during manic episodes and reduced hedonic capacity during depressive episodes, indicating that BPD might involve altered reward processing. Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms. Methods: Eighteen medicated BPD subjects and 25 demographically matched comparison subjects performed a probabilistic reward task. To identify putative dysfunctions in reward processing irrespective of mood state, primary analyses focused on euthymic BPD subjects (n = 13). With signal-detection methodologies, response bias toward a more frequently rewarded stimulus was used to objectively assess the participants' propensity to modulate behavior as a function of reinforcement history. Results: Relative to comparison subjects, euthymic BPD subjects showed a reduced and delayed acquisition of response bias toward the more frequently rewarded stimulus, which was partially due to increased sensitivity to single rewards of the disadvantageous stimulus. Analyses considering the entire BPD sample revealed that reduced reward learning correlated with self-reported anhedonic symptoms, even after adjusting for residual manic and anxious symptoms and general distress. Conclusions: The present study provides preliminary evidence indicating that BPD, even during euthymic states, is characterized by dysfunctional reward learning in situations requiring integration of reinforcement information over time and thus offers initial insights about the potential source of dysfunctional reward processing in this disorder.Psycholog

Dynamic distribution of the replacement histone variant H3.3 in the mouse oocyte and preimplantation embryos

Upon fertilization, the gametes undergo a drastic reprogramming that includes changes in DNA methylation and histone modifications. Currently, it is not known whether replacement of the major histones by histone variants is also involved in these processes. Here we have examined the expression and localization of the histone variant H3.3 in early mouse embryogenesis. We show that H3.3 is present in the oocyte as a maternal factor. It is then incorporated preferentially into the male pronucleus before genome activation, pointing towards an asymmetry in histone composition between the two pronuclei. This is in line with the male pronucleus bearing transcriptional activation first. The same distribution was observed when we followed the localisation of a tagged version of H3.3. We detected H3.3 in the nuclei of mouse embryos in all of the stages analysed, from the zygote to the blastocyst stage, suggesting that the epigenetic mechanisms in the early embryo not only involve changes in histone modifications but may also include histone replacement

Individual Differences in Reinforcement Learning: Behavioral, Electrophysiological, and Neuroimaging Correlates

During reinforcement learning, phasic modulations of activity in midbrain dopamine neurons are conveyed to the dorsal anterior cingulate Cortex (dACC) and basal ganglia (BG) and serve to guide adaptive responding. While the animal literature supports a role for the dACC in integrating reward history over time, most human electrophysiological Studies of dACC function have focused on responses to single positive and negative outcomes. The present electrophysiological study investigated the role of the dACC in probabilistic reward learning in healthy subjects using a task that required integration of reinforcement history over time. We recorded the feedback-related negativity (FRN) to reward feedback in subjects who developed a response bias toward a more frequently rewarded ("rich") stimulus ("learners") versus subjects who did not ("non-learners"). Compared to non-learners, learners showed more positive (i.e., smaller) FRNs and greater dACC activation upon receiving reward for correct identification of the rich stimulus. In addition, dACC activation and a bias to select the rich Stimulus were positively correlated. The same participants also completed a monetary incentive delay (MID) task administered during functional magnetic resonance imaging. Compared to non-learners, learners displayed stronger BG responses to reward in the MID task. These findings raise the possibility that learners in the probabilistic reinforcement task were characterized by stronger dACC and BG responses to rewarding outcomes. Furthermore, these results highlight the importance of the dACC to probabilistic reward learning in humans.Psycholog

Bone morphogenetic protein 4 signaling regulates development of the anterior visceral endoderm in the mouse embryo

The extraembryonic ectoderm (ExE) of the mouse conceptus is known to play a role in embryo patterning by signaling to the underlying epiblast and surrounding visceral endoderm. Bmp4 is one of the key ExE signaling molecules and has been recently implicated to participate in regulating development and migration of the anterior visceral endoderm (AVE). However, it remains unclear when exactly BMP4 signaling starts to regulate AVE positioning. To examine this, we have chosen to affect BMP4 function at two different time points, at embryonic day 5.25 (E5.25), thus before AVE migration, and E5.75, just after AVE migration. To this end, an RNAi technique was used, which consisted of the injection of Bmp4 dsRNA into the proamniotic cavity of the egg cylinder followed by its targeted electroporation into the ExE. This resulted in specific knockdown of Bmp4. It was found that Bmp4 RNAi at E5.25, but not at E5.75, led to an abnormal pattern of expression of the AVE marker Cerberus‐like. Thus, BMP4 signaling appears to affect the expression of Cer1 at a specific time window. This RNAi approach provides a convenient means to study spatial and temporal function of genes shortly after embryo implantation

Histone arginine methylation regulates pluripotency in the early mouse embryo

It has been generally accepted that the mammalian embryo starts its development with all cells identical, and only when inside and outside cells form do differences between cells first emerge. However, recent findings show that cells in the mouse embryo can differ in their developmental fate and potency as early as the four-cell stage1,2,3,4. These differences depend on the orientation and order of the cleavage divisions that generated them2,5. Because epigenetic marks are suggested to be involved in sustaining pluripotency6,7, we considered that such developmental properties might be achieved through epigenetic mechanisms. Here we show that modification of histone H3, through the methylation of specific arginine residues, is correlated with cell fate and potency. Levels of H3 methylation at specific arginine residues are maximal in four-cell blastomeres that will contribute to the inner cell mass (ICM) and polar trophectoderm and undertake full development when combined together in chimaeras. Arginine methylation of H3 is minimal in cells whose progeny contributes more to the mural trophectoderm and that show compromised development when combined in chimaeras. This suggests that higher levels of H3 arginine methylation predispose blastomeres to contribute to the pluripotent cells of the ICM. We confirm this prediction by overexpressing the H3-specific arginine methyltransferase CARM1 in individual blastomeres and show that this directs their progeny to the ICM and results in a dramatic upregulation of Nanog and Sox2. Thus, our results identify specific histone modifications as the earliest known epigenetic marker contributing to development of ICM and show that manipulation of epigenetic information influences cell fate determination