RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation

Summary: X-linked intellectual disability (XLID) is a heterogeneous syndrome affecting mainly males. Human genetics has identified >100 XLID genes, although the molecular and developmental mechanisms underpinning this disorder remain unclear. Here, we employ an embryonic stem cell model to explore developmental functions of a recently identified XLID gene, the RNF12/RLIM E3 ubiquitin ligase. We show that RNF12 catalytic activity is required for proper stem cell maintenance and neural differentiation, and this is disrupted by patient-associated XLID mutation. We further demonstrate that RNF12 XLID mutations specifically impair ubiquitylation of developmentally relevant substrates. XLID mutants disrupt distinct RNF12 functional modules by either inactivating the catalytic RING domain or interfering with a distal regulatory region required for efficient ubiquitin transfer. Our data thereby uncover a key function for RNF12 E3 ubiquitin ligase activity in stem cell and neural development and identify mechanisms by which this is disrupted in intellectual disability. : Bustos et al. show that the RNF12 E3 ubiquitin ligase regulates stem cell maintenance and neuronal differentiation. They demonstrate that RNF12/RLIM mutations identified in X-linked intellectual disability patients disrupt regions required for catalytic activity, which leads to compromised stem cell maintenance and abnormal neural differentiation. Keywords: ubiquitin, protein ubiquitylation, E3 ubiquitin ligase, proteasomal degradation, RNF12/RLIM, intellectual disability, X-linked intellectual disability, embryonic stem cells, neural differentiatio

Effects of syntactic context on eye movements during reading

Previous research has demonstrated that properties of a currently fixated word and of adjacent words influence eye movement control in reading. In contrast to such local effects, little is known about the global effects on eye movement control, for example global adjustments caused by processing difficulty of previous sentences. In the present study, participants read text passages in which voice (active vs. passive) and sentence structure (embedded vs. non-embedded) were manipulated. These passages were followed by identical target sentences. The results revealed effects of previous sentence structure on gaze durations in the target sentence, implying that syntactic properties of previously read sentences may lead to a global adjustment of eye movement control

Alignment to the Actions of a Robot

Alignment is a phenomenon observed in human conversation: Dialog partners’ behavior converges in many respects. Such alignment has been proposed to be automatic and the basis for communicating successfully. Recent research on human–computer dialog promotes a mediated communicative design account of alignment according to which the extent of alignment is influenced by interlocutors’ beliefs about each other. Our work aims at adding to these findings in two ways. (a) Our work investigates alignment of manual actions, instead of lexical choice. (b) Participants interact with the iCub humanoid robot, instead of an artificial computer dialog system. Our results confirm that alignment also takes place in the domain of actions. We were not able to replicate the results of the original study in general in this setting, but in accordance with its findings, participants with a high questionnaire score for emotional stability and participants who are familiar with robots align their actions more to a robot they believe to be basic than to one they believe to be advanced. Regarding alignment over the course of an interaction, the extent of alignment seems to remain constant, when participants believe the robot to be advanced, but it increases over time, when participants believe the robot to be a basic version

Ubiquitin transfer by a RING E3 ligase occurs from a closed E2~ubiquitin conformation

Funding: Investigator Award from the Wellcome Trust (098391/Z/12/Z) and (217196/Z/19/Z) and a Programme grant from Cancer Research UK (C434/A21747) to R.T.H.; J.C.P. thanks the University of St Andrews for financial support.Based on extensive structural analysis it was proposed that RING E3 ligases prime the E2~ubiquitin conjugate (E2~Ub) for catalysis by locking it into a closed conformation, where ubiquitin is folded back onto the E2 exposing the restrained thioester bond to attack by substrate nucleophile. However the proposal that the RING dependent closed conformation of E2~Ub represents the active form that mediates ubiquitin transfer has yet to be experimentally tested. To test this hypothesis we use single molecule Förster Resonance Energy Transfer (smFRET) to measure the conformation of a FRET labelled E2~Ub conjugate, which distinguishes between closed and alternative conformations. We describe a real-time FRET assay with a thioester linked E2~Ub conjugate to monitor single ubiquitination events and demonstrate that ubiquitin is transferred to substrate from the closed conformation. These findings are likely to be relevant to all RING E3 catalysed reactions ligating ubiquitin and other ubiquitin-like proteins (Ubls) to substrates.Publisher PDFPeer reviewe

The use of reported speech in children's narratives: a priming study

This study investigated the long-term effects of structural priming on children’s use of indirect speech clauses in a narrative context. Forty-two monolingual English-speaking five-year-olds in two primary classrooms took part in a story re-telling task including reported speech. Testing took place in three individual sessions (pre-test, post-test1, post-test2) and the priming phase was conducted in 10 group priming sessions. During the priming phase the two classrooms were randomly allocated to one of two conditions where, over the course of two weeks, the children heard 10 different stories that included 30 tokens of either indirect or direct speech. In the pre-test session we collected measures of receptive vocabulary (BPVS-3) and expressive grammar (Formulated Sentences sub-test, CELF4-UK). There was a significant effect of input manipulation that was maintained for up to ten weeks after the training. Expressive grammatical skills were positively correlated with the likelihood of using indirect speech one week after the end of the language intervention

Turning a lost reef ecosystem into a national restoration program

Achieving a sustainable socioecological future now requires large-scale environmental repair across legislative borders. Yet, enabling large-scale conservation is complicated by policy-making processes that are disconnected from socioeconomic interests, multiple sources of knowledge, and differing applications of policy. We considered how a multidisciplinary approach to marine habitat restoration generated the scientific evidence base, community support, and funding needed to begin the restoration of a forgotten, functionally extinct shellfish reef ecosystem. The key actors came together as a multidisciplinary community of researchers, conservation practitioners, recreational fisher communities, and government bodies that collaborated across sectors to rediscover Australia's lost shellfish reefs and communicate the value of its restoration. Actions undertaken to build a case for large-scale marine restoration included synthesizing current knowledge on Australian shellfish reefs and their historical decline, using this history to tell a compelling story to spark public and political interest, integrating restoration into government policy, and rallying local support through community engagement. Clearly articulating the social, economic, and environmental business case for restoration led to state and national funding for reef restoration to meet diverse sustainability goals (e.g., enhanced biodiversity and fisheries productivity) and socioeconomic goals (e.g., job creation and recreational opportunities). A key lesson learned was the importance of aligning project goals with public and industry interests so that projects could address multiple political obligations. This process culminated in Australia's largest marine restoration initiative and shows that solutions for large-scale ecosystem repair can rapidly occur when socially valued science acts on political opportunities