Mammalian cadherins and protocadherins: about cell death, synapses and processing.

Cadherins have been known for a long time to be key elements in many important biological processes. In particular, the role of classical cadherins in mediating adhesion has been examined in great detail. Over recent years, the accumulation of experimental tools and mice mutants has allowed more refined analysis of cadherin functions, and new aspects such as signaling and synapse dynamics have become the center of interest. In addition, the study of mice lacking the entire protocadherin-gamma cluster shed the first light on a possible novel function of members of this cadherin family in synapse formation and cell survival during development.

Political uncertainty moderates neural evaluation of incongruent policy positions.

Uncertainty has been shown to impact political evaluation, yet the exact mechanisms by which uncertainty affects the minds of citizens remain unclear. This experiment examines the neural underpinnings of uncertainty in political evaluation using functional magnetic resonance imaging (fMRI). During fMRI, participants completed an experimental task where they evaluated policy positions attributed to hypothetical political candidates. Policy positions were either congruent or incongruent with candidates' political party affiliation and presented with varying levels of certainty. Neural activity was modelled as a function of uncertainty and incongruence. Analyses suggest that neural activity in brain regions previously implicated in affective and evaluative processing (anterior cingulate cortex, insular cortex) differed as a function of the interaction between uncertainty and incongruence, such that activation in these areas was greatest when information was both certain and incongruent, and uncertainty influenced processing differently as a function of the valence of the attached information. These findings suggest that individuals are attuned to uncertainty in the stated issue positions of politicians, and that the neural processing of this uncertainty is dependent on congruence of these positions with expectations based on political party identification. Implications for the study of emotion and politics and political cognition are discussed. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.

Perceived Threat Associated with Police Officers and Black Men Predicts Support for Policing Policy Reform.

Racial disparities in policing and recent high-profile incidents resulting in the deaths of Black men have ignited a national debate on policing policies. Given evidence that both police officers and Black men may be associated with threat, we examined the impact of perceived threat on support for reformed policing policies. Across three studies we found correlational evidence that perceiving police officers as threatening predicts increased support for reformed policing practices (e.g., limiting the use of lethal force and matching police force demographics to those of the community). In contrast, perceiving Black men as threatening predicted reduced support for policing policy reform. Perceived threat also predicted willingness to sign a petition calling for police reform. Experimental evidence indicated that priming participants to associate Black men with threat could also reduce support for policing policy reform, and this effect was moderated by internal motivation to respond without prejudice. Priming participants to associate police officers with threat did not increase support for policing policy reform. Results indicate that resistance to policing policy reform is associated with perceiving Black men as threatening. Moreover, findings suggest that publicizing racially charged police encounters, which may conjure associations between Black men and threat, could reduce support for policing policy reform.

Morpholino oligonucleotide-triggered knockdown reveals a role for maternal E-cadherin during early mouse development.

We report that gene silencing via intracytoplasmic microinjections of morpholino-modified antisense oligonucleotides is an effective and reproducible method to study both maternal and zygotic gene functions during early and late stages of mouse preimplantation development. The zygotic expression of the beta-geo transgene in the ROSA26 mouse strain could be inhibited until at least the early blastula stages. Thus morpholino-triggered gene inactivation appears to be a useful method to study the functional role of genes in preimplantation development. Using this approach, we have investigated a potential role of maternal expression of Cdh1, the gene encoding the cell-adhesion molecule E-cadherin. Inhibition of translation of maternal E-cadherin mRNA causes a developmental arrest at the two-cell stage. BrUTP incorporation assays indicated that this developmental defect cannot be explained by a general failure in transcriptional activity. This defect is reversible since E-cadherin mRNA can rescue the affected embryos, suggesting that a functional adhesion complex, present at the junction between blastomeres, is a prerequisite for the normal development of the mouse preimplantation embryo. Our study thus reveals a previously unanticipated role of maternal E-cadherin during early stages of mouse development.

The importance of moral construal: moral versus non-moral construal elicits faster, more extreme, universal evaluations of the same actions.

Over the past decade, intuitionist models of morality have challenged the view that moral reasoning is the sole or even primary means by which moral judgments are made. Rather, intuitionist models posit that certain situations automatically elicit moral intuitions, which guide moral judgments. We present three experiments showing that evaluations are also susceptible to the influence of moral versus non-moral construal. We had participants make moral evaluations (rating whether actions were morally good or bad) or non-moral evaluations (rating whether actions were pragmatically or hedonically good or bad) of a wide variety of actions. As predicted, moral evaluations were faster, more extreme, and more strongly associated with universal prescriptions-the belief that absolutely nobody or everybody should engage in an action-than non-moral (pragmatic or hedonic) evaluations of the same actions. Further, we show that people are capable of flexibly shifting from moral to non-moral evaluations on a trial-by-trial basis. Taken together, these experiments provide evidence that moral versus non-moral construal has an important influence on evaluation and suggests that effects of construal are highly flexible. We discuss the implications of these experiments for models of moral judgment and decision-making.

Regulated ADAM10-dependent ectodomain shedding of gamma-protocadherin C3 modulates cell-cell adhesion.

Gamma-protocadherins (Pcdh gamma) are type I transmembrane proteins, which are most notably expressed in the nervous system. They are enriched at synapses and involved in synapse formation, specification, and maintenance. In this study, we show that Pcdh gamma C3 and Pcdh gamma B4 are specifically cleaved within their ectodomains by the disintegrin and metalloprotease ADAM10. Analysis of ADAM10-deficient fibroblasts and embryos, inhibitor studies, as well as RNA interference-mediated down-regulation demonstrated that ADAM10 is not only responsible for the constitutive but also for the regulated shedding of these proteins in fibroblasts and in neuronal cells. In contrast to N-cadherin shedding, which was activated by N-methyl-D-aspartic acid receptor activation in neuronal cells, Pcdh gamma shedding was induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate stimulation, suggesting differential regulation mechanisms of cadherin-mediated functions at synapses. Cell aggregation assays in the presence or absence of metalloprotease inhibitors strongly suggest that the ectodomain shedding events modulate the cell adhesion role of Pcdh gamma. The identification of ADAM10 as the protease responsible for constitutive and regulated Pcdh gamma shedding may therefore provide new insight into the regulation of Pcdh gamma functions.

Presenilin-dependent processing and nuclear function of gamma-protocadherins.

The recently described protocadherin gene clusters encode cadherin-related proteins, which are highly expressed in the vertebrate nervous system. Here, we report biochemical studies addressing proteolytic processing of gamma-protocadherins. These type-I transmembrane proteins are cleaved by a metalloproteinase in vivo, generating a soluble extracellular fragment and a carboxyl-terminal fragment associated with the cellular membrane. In addition, we show that the carboxyl-terminal fragment is a substrate for further cleavage mediated by presenilin. Consequently, accumulation of the fragment is found when gamma-secretase is inactivated either by the specific presenilin-inhibitor L685,458 or in double mutant murine embryonic fibroblasts lacking both presenilin genes. The gamma-secretase-generated carboxyl-terminal fragment is largely unstable but accumulates when proteasomal degradation is inhibited. Interestingly, the proteolytic fragment generated by gamma-secretase can localize to the nucleus. This is the first report providing experimental evidence for a cell surface receptor signaling function of protocadherins regulated by proteolytic events.

BiP is feed-back regulated by control of protein translation efficiency.

The lumenal endoplasmic reticulum (ER) protein BiP, among its other functions, is believed to serve as an ER stress sensor, triggering the so-called 'unfolded protein response' or UPR. For this role, BiP levels are critical. Indeed, here we show that BiP expression is tightly controlled at a post-transcriptional level. Thus, an artificial increase in cellular BiP mRNA does not lead to increased synthesis of BiP in unstressed cells, and, consequently, protein levels remain constant. Under ER stress conditions, however, this homeostatic restriction is alleviated, and independent of transcript levels, the translation efficiency of BiP transcripts is enhanced, allowing the cells to produce more protein. We additionally show that this regulation is independent of elements in the 5' and 3' UTR of BiP mRNA, which rather points to a novel type of translational feedback control. BiP is the first example of a lumenal protein whose expression is controlled at a translational level. The implications of these findings with respect to cellular stress are discussed.