17 research outputs found
Correction of fragile X syndrome in mice
SummaryFragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders
Fragile x syndrome and autism: from disease model to therapeutic targets
Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism
Cephalopod-omics: emerging fields and technologies in cephalopod biology
14 pages, 1 figure.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution LicenseFew animal groups can claim the level of wonder that cephalopods instill in the minds of researchers and the general public. Much of cephalopod biology, however, remains unexplored: the largest invertebrate brain, difficult husbandry conditions, and complex (meta-)genomes, among many other things, have hindered progress in addressing key questions. However, recent technological advancements in sequencing, imaging, and genetic manipulation have opened new avenues for exploring the biology of these extraordinary animals. The cephalopod molecular biology community is thus experiencing a large influx of researchers, emerging from different fields, accelerating the pace of research in this clade. In the first post-pandemic event at the Cephalopod International Advisory Council (CIAC) conference in April 2022, over 40 participants from all over the world met and discussed key challenges and perspectives for current cephalopod molecular biology and evolution. Our particular focus was on the fields of comparative and regulatory genomics, gene manipulation, single-cell transcriptomics, metagenomics, and microbial interactions. This article is a result of this joint effort, summarizing the latest insights from these emerging fields, their bottlenecks, and potential solutions. The article highlights the interdisciplinary nature of the cephalopod-omics community and provides an emphasis on continuous consolidation of efforts and collaboration in this rapidly evolving fieldPeer reviewe
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Editorial: Essential Pathways and Circuits of Autism Pathogenesis
The Centers for Disease Control and Prevention estimate that 1 in 68 children in the United states is afflicted with autism spectrum disorders (ASD), yet at this time, there is no cure for the disease. Autism is characterized by delays in the development of many basic skills, most notably the ability to socialize and adapt to novelty. The condition is typically identified in children around 3 years of age, however the high heritability of autism suggests that the disease process begins at conception. The identification of over 500 ASD risk genes, has enabled the molecular genetic dissection of the pathogenesis of the disease in model organisms such as mice. Despite the genetic heterogeneity of ASD etiology, converging evidence suggests that these disparate genetic lesions may result in the disruption of a limited number of key biochemical pathways or circuits. Classification of patients into groups by pathogenic rather than etiological categories, will likely aid future therapeutic development and clinical trials. In this set of papers, we explore the existing evidence supporting this view. Specifically, we focus on biochemical cascades such as mTOR and ERK signaling, the mRNA network bound by FMRP and UBE3A, dorsal and ventral striatal circuits, cerebellar circuits, hypothalamic projections, as well as prefrontal and anterior cingulate cortical circuits. Special attention will be given to studies that demonstrate the necessity and/or sufficiency of genetic disruptions (e.g. by molecular deletion and/or replacement) in these pathways and circuits for producing characteristic behavioral features of autism. Necessarily these papers will be heavily weighted towards basic mechanisms elucidated in animal models, but may also include investigations in patients
Supplementary data: The transcription factor Zic2 designates the uncrossed retinal ganglion cell axon projection
Experimental Procedures for Supplemental Figure:
Double-stranded Zic2 and Zic2 mutant decoy DNA were prepared by annealing complementary single strands with the follow sequences: 5′-TCTTGGGTGGTCTCCGGAGACCACCCAAGA (for Zic2 decoy) and 5′-TCTTGAGTGAACTCCGGAGTTCACTCAAGA (for Zic2M decoy) as a negative control (Mizugishi et al., 2001). We utilized unlabeled and also Texas-red-tagged oligonucleotides (Invitrogen) to monitor DNA entry into cells. The terminal four bases on either site of the molecule were linked by phosphorothioate esters for added stability. Retinal explants were exposed to serial concentrations (0, 10, 100, and 200 μM) of decoy DNA combined with serial concentrations of serum-free medium (SFM) plus Fungene 6 transfection reagent (Roche) and incubated for 1 hr 30 min at 37°C. The explants were then washed several times in SFM, plated on D-polylysine/laminin, and incubated at 37°C, and dissociated chiasm cells were added to the cultures 2 hr later. They were then immunolabeled with α-neurofilament and explant outgrowth quantified, as indicated in Experimental Procedures.Figure S1. Zic2 Is Necessary for Ventrotemproal (VT) RGCs to Respond Negatively to Cues from the Chiasm Midline In Vitro.
(A) Retinal explants grown on dissociated chiasm cells and immunostained with α-neurofilament. Representative images of dorsotemporal (DT) (a–d) and VT (e–h) retinal explants that were untransfected (a and e) or incubated with lipofectamine (b and f), Zic2 decoy oligos (c and g), or Zic2-mutant-decoy oligos (d and h) and subsequently cocultured with dissociated chiasm cells. Scale bar: 100 μm.
(B) Quantification of area occupied by axons of DT (black columns) or VT (white columns) retinal explants that were untransfected or incubated with lipofectamine, Zic2-decoy oligos, or mutant-Zic2-decoy oligos, and then cocultured with dissociated chiasm cells. Left panels and graph: transfection of Zic2-decoy oligos does not affect the outgrowth in DT neurites (p > 0.2). Right panels and graph: transfection of Zic2-decoy oligos leads to increased growth of VT neurites. (*p < 0.05 compared with VT explants incubated with the lipofection agent alone or transfected with Zic2M-decoy). Number above bars indicates number of explants.Peer reviewe
A Computational Model of Trust-, Pupil-, and Motivation Dynamics
Autonomous machines are in the near future likely to increasingly interact with humans, and carry out their functions outside controlled settings. Both of these developments increase the requirements of machines to be trustworthy to humans. In this work, we argue that machines may also benefit from being able to explicitly build or withdraw trust with specific humans. The latter is relevant in situations where the integrity of an autonomous system is compromised, or if humans display untrustworthy behaviour towards the system. Examples of systems that could benefit might be delivery robots, maintenance robots, or autonomous taxis. This work contributes by presenting a biologically plausible model of unconditional trust dynamics, which simulates trust building based on familiarity, but which can be modulated by painful and gentle touch. The model displays interactive behaviour by being able to realistically control pupil dynamics, as well as determine approach and avoidance motivation