eLife: latest articles

Intact synapse structure and function after combined knockout of PTPδ, PTPσ and LAR

Javier_EmperadorMelero@hms.harvard.edu (Giovanni de Nola) — Wed, 03 Mar 2021 00:00:00 +0000

It has long been proposed that Leukocyte common Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs) are cell-adhesion proteins that control synapse assembly. Their synaptic nanoscale localization, however, is not established, and synapse fine structure after knockout of the three vertebrate LAR-RPTPs (PTPδ, PTPσ and LAR) has not been tested. Here, superresolution microscopy reveals that PTPδ localizes to the synaptic cleft precisely apposed to postsynaptic scaffolds of excitatory and inhibitory synapses. We next assessed synapse structure in newly generated triple-conditional knockout mice for PTPδ, PTPσ and LAR, complementing a recent independent study of synapse function after LAR-RPTP ablation (Sclip and Südhof, 2020). While mild effects on synaptic vesicle clustering and active zone architecture were detected, synapse numbers and their overall structure were unaffected, membrane anchoring of the active zone persisted, and vesicle docking and release were normal. Hence, despite their localization at synaptic appositions, LAR-RPTPs are dispensable for presynapse structure and function.

A mobile genetic element increases bacterial host fitness by manipulating development

avigdor@gmail.com (Alan D Grossman) — Wed, 03 Mar 2021 00:00:00 +0000

Horizontal gene transfer is a major force in bacterial evolution. Mobile genetic elements are responsible for much of horizontal gene transfer and also carry beneficial cargo genes. Uncovering strategies used by mobile genetic elements to benefit host cells is crucial for understanding their stability and spread in populations. We describe a benefit that ICEBs1, an integrative and conjugative element of Bacillus subtilis, provides to its host cells. Activation of ICEBs1 conferred a frequency-dependent selective advantage to host cells during two different developmental processes: biofilm formation and sporulation. These benefits were due to inhibition of biofilm-associated gene expression and delayed sporulation by ICEBs1-containing cells, enabling them to exploit their neighbors and grow more prior to development. A single ICEBs1 gene, devI (formerly ydcO), was both necessary and sufficient for inhibition of development. Manipulation of host developmental programs allows ICEBs1 to increase host fitness, thereby increasing propagation of the element.

Dynamic Na⁺/H⁺ Exchanger 1 (NHE1):Calmodulin complexes of varying stoichiometry and structure regulate Ca²⁺-dependent NHE1 activation

bbk@bio.ku.dk (Andreas Prestel) — Wed, 03 Mar 2021 00:00:00 +0000

Calmodulin (CaM) engages in Ca²⁺-dependent interactions with numerous proteins, including a still incompletely understood physical and functional interaction with the human Na⁺/H⁺-exchanger NHE1. Using nuclear magnetic resonance (NMR) spectroscopy, isothermal titration calorimetry, and fibroblasts stably expressing wildtype and mutant NHE1, we discovered multiple accessible states of this functionally important complex existing in different NHE1:CaM stoichiometries and structures. We determined the NMR solution structure of a ternary complex in which CaM links two NHE1 cytosolic tails. In vitro, stoichiometries and affinities could be tuned by variations in NHE1:CaM ratio and calcium ([Ca²⁺]) and by phosphorylation of S648 in the first CaM-binding a-helix. In cells, Ca²⁺-CaM-induced NHE1 activity was reduced by mimicking S648 phosphorylation and by mutation of the first CaM-binding a-helix, whereas it was unaffected by inhibition of Akt, one of several kinases phosphorylating S648. Our results demonstrate a diversity of NHE1:CaM interaction modes and suggest that CaM may contribute to NHE1 dimerization and thereby augment NHE1 regulation. We propose that a similar structural diversity is of relevance to many other CaM complexes.

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

alessandra.renieri@unisi.it (Alessandra Renieri) — Tue, 02 Mar 2021 00:00:00 +0000

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.

Loss of circadian protection against influenza infection in adult mice exposed to hyperoxia as neonates

SenguptaS@email.chop.edu (Amita Sehgal) — Tue, 02 Mar 2021 00:00:00 +0000

Adverse early-life exposures have a lasting negative impact on health. Neonatal hyperoxia that is a risk factor for bronchopulmonary dysplasia confers susceptibility to influenza A virus (IAV) infection later in life. Given our previous findings that the circadian clock protects against IAV, we asked if the long-term impact of neonatal hyperoxia vis-à-vis IAV infection includes circadian disruption. Here, we show that neonatal hyperoxia abolishes the clock-mediated time of day protection from IAV in mice, independent of viral burden through host tolerance pathways. We discovered that the lung intrinsic clock (and not the central or immune clocks) mediated this dysregulation. Loss of circadian protein, Bmal1, in alveolar type 2 (AT2) cells recapitulates the increased mortality, loss of temporal gating, and other key features of hyperoxia-exposed animals. Our data suggest a novel role for the circadian clock in AT2 cells in mediating long-term effects of early-life exposures to the lungs.

Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

turrigiano@brandeis.edu (Brian A Cary) — Tue, 02 Mar 2021 00:00:00 +0000

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

In vivo reconstitution finds multivalent RNA-RNA interactions as drivers of mesh-like condensates

maweirui@zju.edu.cn (Christine Mayr) — Tue, 02 Mar 2021 00:00:00 +0000

Liquid-like condensates have been thought to be sphere-like. Recently, various condensates with filamentous morphology have been observed in cells. One such condensate is the TIS granule network that shares a large surface area with the rough endoplasmic reticulum and is important for membrane protein trafficking. It has been unclear how condensates with mesh-like shapes, but dynamic protein components are formed. In vitro and in vivo reconstitution experiments revealed that the minimal components are a multivalent RNA-binding protein that concentrates RNAs that are able to form extensive intermolecular mRNA-mRNA interactions. mRNAs with large unstructured regions have a high propensity to form a pervasive intermolecular interaction network that acts as condensate skeleton. The underlying RNA matrix prevents full fusion of spherical liquid-like condensates, thus driving the formation of irregularly shaped membraneless organelles. The resulting large surface area may promote interactions at the condensate surface and at the interface with other organelles.

Functional specialization within the inferior parietal lobes across cognitive domains

danilo.bzdok@mcgill.ca (Danilo Bzdok) — Tue, 02 Mar 2021 00:00:00 +0000

The inferior parietal lobe (IPL) is a key neural substrate underlying diverse mental processes, from basic attention to language and social cognition, that define human interactions. Its putative domain-global role appears to tie into poorly understood differences between cognitive domains in both hemispheres. Across attentional, semantic, and social cognitive tasks, our study explored functional specialization within the IPL. The task specificity of IPL subregion activity was substantiated by distinct predictive signatures identified by multivariate pattern-learning algorithms. Moreover, the left and right IPL exerted domain-specific modulation of effective connectivity among their subregions. Task-evoked functional interactions of the anterior and posterior IPL subregions involved recruitment of distributed cortical partners. While anterior IPL subregions were engaged in strongly lateralized coupling links, both posterior subregions showed more symmetric coupling patterns across hemispheres. Our collective results shed light on how under-appreciated functional specialization in the IPL supports some of the most distinctive human mental capacities.

New light shed on the early evolution of limb-bone growth plate and bone marrow

jordi.estefa@gmail.com (Alice M Clement) — Tue, 02 Mar 2021 00:00:00 +0000

The production of blood cells (haematopoiesis) occurs in the limb bones of most tetrapods but is absent in the fin bones of ray-finned fish. When did long bones start producing blood cells? Recent hypotheses suggested that haematopoiesis migrated into long bones prior to the water-to-land transition and protected newly-produced blood cells from harsher environmental conditions. However, little fossil evidence to support these hypotheses has been provided so far. Observations of the humeral microarchitecture of stem-tetrapods, batrachians, and amniotes were performed using classical sectioning and three-dimensional synchrotron virtual histology. They show that Permian tetrapods seem to be among the first to exhibit a centralised marrow organisation, which allows haematopoiesis as in extant amniotes. Not only does our study demonstrate that long-bone haematopoiesis was probably not an exaptation to the water-to-land transition but it sheds light on the early evolution of limb-bone development and the sequence of bone-marrow functional acquisitions.

Self-blinding citizen science to explore psychedelic microdosing

balazs.szigeti07@imperial.ac.uk (Allan Blemings) — Tue, 02 Mar 2021 00:00:00 +0000

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.

Endoglycan plays a role in axon guidance by modulating cell adhesion

esther.stoeckli@mls.uzh.ch (Alexandre Dumoulin) — Tue, 02 Mar 2021 00:00:00 +0000

Axon navigation depends on the interactions between guidance molecules along the trajectory and specific receptors on the growth cone. However, our in vitro and in vivo studies on the role of Endoglycan demonstrate that in addition to specific guidance cue – receptor interactions, axon guidance depends on fine-tuning of cell-cell adhesion. Endoglycan, a sialomucin, plays a role in axon guidance in the central nervous system of chicken embryos, but it is neither an axon guidance cue nor a receptor. Rather Endoglycan acts as a negative regulator of molecular interactions based on evidence from in vitro experiments demonstrating reduced adhesion of growth cones . In the absence of Endoglycan, commissural axons fail to properly navigate the midline of the spinal cord. Taken together, our in vivo and in vitro results support the hypothesis that Endoglycan acts as a negative regulator of cell-cell adhesion, in commissural axon guidance.

Genomic epidemiology of COVID-19 in care homes in the East of England

will.l.hamilton@gmail.com (Alex Alderton) — Tue, 02 Mar 2021 00:00:00 +0000

COVID-19 poses a major challenge to care homes, as SARS-CoV-2 is readily transmitted and causes disproportionately severe disease in older people. Here, 1,167 residents from 337 care homes were identified from a dataset of 6,600 COVID-19 cases from the East of England. Older age and being a care home resident were associated with increased mortality. SARS-CoV-2 genomes were available for 700 residents from 292 care homes. By integrating genomic and temporal data, 409 viral clusters within the 292 homes were identified, indicating two different patterns - outbreaks among care home residents and independent introductions with limited onward transmission. Approximately 70% of residents in the genomic analysis were admitted to hospital during the study, providing extensive opportunities for transmission between care homes and hospitals. Limiting viral transmission within care homes should be a key target for infection control to reduce COVID-19 mortality in this population.

Asking questions of psychedelic microdosing

lcameron@ucdavis.edu (Lindsay P Cameron) — Tue, 02 Mar 2021 00:00:00 +0000

A citizen science approach to research has shown that the improvements in mood and cognition associated with psychedelic microdosing are likely due to a placebo effect.

Unraveling the history of limb bones

holly.ballard@okstate.edu (Holly N Woodward) — Tue, 02 Mar 2021 00:00:00 +0000

Ancient fossils give clues as to when features of modern tetrapod bones emerged.

Integrative frontal-parietal dynamics supporting cognitive control

derek.evan.nee@gmail.com (Derek Evan Nee) — Tue, 02 Mar 2021 00:00:00 +0000

Coordinating among the demands of the external environment and internal plans requires cognitive control supported by a fronto-parietal control network (FPCN). Evidence suggests that multiple control systems span the FPCN whose operations are poorly understood. Previously (Nee and D'Esposito, 2016; 2017), we detailed frontal dynamics that support control processing, but left open their role in broader cortical function. Here, I show that the FPCN consists of an external/present-oriented to internal/future-oriented cortical gradient extending outwardly from sensory-motor cortices. Areas at the ends of this gradient act in a segregative manner, exciting areas at the same level, but suppressing areas at different levels. By contrast, areas in the middle of the gradient excite areas at all levels, promoting integration of control processing. Individual differences in integrative dynamics predict higher-level cognitive ability and amenability to neuromodulation. These data suggest that an intermediary zone within the FPCN underlies integrative processing that supports cognitive control.

Bone age is not just for kids

jcauley@edc.pitt.edu (Dolores M Shoback) — Tue, 02 Mar 2021 00:00:00 +0000

More informed discussions between physicians and older adults about the consequences of an initial osteoporotic fracture could encourage more patients to consider treatments that protect against future fracture.

tRNA sequences can assemble into a replicator

dieter.braun@lmu.de (Alexandra Kühnlein) — Tue, 02 Mar 2021 00:00:00 +0000

Can replication and translation emerge in a single mechanism via self-assembly? The key molecule, transfer RNA (tRNA), is one of the most ancient molecules and contains the genetic code. Our experiments show how a pool of oligonucleotides, adapted with minor mutations from tRNA, spontaneously formed molecular assemblies and replicated information autonomously using only reversible hybridization under thermal oscillations. The pool of cross-complementary hairpins self-selected by agglomeration and sedimentation. The metastable DNA hairpins bound to a template and then interconnected by hybridization. Thermal oscillations separated replicates from their templates and drove an exponential, cross-catalytic replication. The molecular assembly could encode and replicate binary sequences with a replication fidelity corresponding to 85–90 % per nucleotide. The replication by a self-assembly of tRNA-like sequences suggests that early forms of tRNA could have been involved in molecular replication. This would link the evolution of translation to a mechanism of molecular replication.

Preliminary paleohistological observations of the StW 573 (‘Little Foot’) skull

aab88@cam.ac.uk (Amélie Beaudet) — Tue, 02 Mar 2021 00:00:00 +0000

Numerous aspects of early hominin biology remain debated or simply unknown. However, recent developments in high-resolution imaging techniques have opened new avenues in the field of paleoanthropology. More specifically, X-ray synchrotron-based analytical imaging techniques have the potential to provide crucial details on the ontogeny, physiology, biomechanics, and biological identity of fossil specimens. Here we present preliminary results of our X-ray synchrotron-based investigation of the skull of the 3.67-million-year-old Australopithecus specimen StW 573 (‘Little Foot’) at the I12 beamline of the Diamond Light Source (United Kingdom). Besides showing fine details of the enamel (i.e., hypoplasias) and cementum (i.e., incremental lines), as well as of the cranial bone microarchitecture (e.g., diploic channels), our synchrotron-based investigation reveals for the first time the 3D spatial organization of the Haversian systems in the mandibular symphysis of an early hominin.

Archaeal chromatin 'slinkies' are inherently dynamic complexes with deflected DNA wrapping pathways

karolin.luger@colorado.edu (Jeff Wereszczynski) — Tue, 02 Mar 2021 00:00:00 +0000

Eukaryotes and many archaea package their DNA with histones. While the four eukaryotic histones wrap ~147 DNA base pairs into nucleosomes, archaeal histones form 'nucleosome-like' complexes that continuously wind between 60 - 500 base pairs of DNA ('archaeasomes'), suggested by crystal contacts and analysis of cellular chromatin. Solution structures of large archaeasomes (>90 DNA base pairs) have never been directly observed. Here, we utilize molecular dynamics simulations, analytical ultracentrifugation, and cryoEM to structurally characterize the solution state of archaeasomes on longer DNA. Simulations reveal dynamics of increased accessibility without disruption of DNA-binding or tetramerization interfaces. Mg²⁺concentration influences compaction, and cryoEM densities illustrate that DNA is wrapped in consecutive substates arranged 90^o out-of-plane with one another. Without ATP-dependent remodelers, archaea may leverage these inherent dynamics to balance chromatin packing and accessibility.

Mapping immune variation and var gene switching in naive hosts infected with Plasmodium falciparum

Alex.Rowe@ed.ac.uk (Adam J Reid) — Tue, 02 Mar 2021 00:00:00 +0000

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease rapidly expand in naive hosts, we found no transcriptional evidence to support this hypothesis. These data indicate that parasite variants that dominate severe malaria do not have an intrinsic growth or survival advantage; instead, they presumably rely upon infection-induced changes in their within-host environment for selection.

Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein

wards10@cardiff.ac.uk (Antony W Oliver) — Mon, 01 Mar 2021 00:00:00 +0000

BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM’s ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.

Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice

vanveen@ucla.edu (Douglas Arneson) — Mon, 01 Mar 2021 00:00:00 +0000

Adjuvant tamoxifen therapy improves survival in breast cancer patients. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are unclear. Here, we show that mice undergoing tamoxifen treatment experience changes in temperature, bone, and movement. Single-cell RNA sequencing reveals that tamoxifen treatment induces widespread gene expression changes in the hypothalamus and preoptic area (hypothalamus-POA). These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus-POA ablates or reverses tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit tamoxifen-induced changes in temperature, bone, or movement. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus-POA and indicate that ERα mediates several physiological effects of tamoxifen treatment in mice.

Bidirectional regulation of glial potassium buffering: glioprotection versus neuroprotection

diantonio@wustl.edu (Aaron DiAntonio) — Mon, 01 Mar 2021 00:00:00 +0000

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A SIK3-regulated gene expression program controls the glial capacity to buffer K⁺ and water in Drosophila, however upstream regulatory mechanisms are unknown. Here we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic GPCR OctbR to upregulate glial buffering capacity, while under pathological K⁺ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway in inactivated. Re-activation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened lifespan in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

bmanning@hsph.harvard.edu (Aaron M Hosios) — Mon, 01 Mar 2021 00:00:00 +0000

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

Neural encoding of actual and imagined touch within human posterior parietal cortex

taflalo@caltech.edu (Carey Y Zhang) — Mon, 01 Mar 2021 00:00:00 +0000

In the human posterior parietal cortex (PPC), single units encode high-dimensional information with partially mixed representations that enable small populations of neurons to encode many variables relevant to movement planning, execution, cognition, and perception. Here, we test whether a PPC neuronal population previously demonstrated to encode visual and motor information is similarly engaged in the somatosensory domain. We recorded neurons within the PPC of a human clinical trial participant during actual touch presentation and during a tactile imagery task. Neurons encoded actual touch at short latency with bilateral receptive fields, organized by body part, and covered all tested regions. The tactile imagery task evoked body part-specific responses that shared a neural substrate with actual touch. Our results are the first neuron-level evidence of touch encoding in human PPC and its cognitive engagement during a tactile imagery task, which may reflect semantic processing, attention, sensory anticipation, or imagined touch.

C. elegans orthologs MUT-7/CeWRN-1 of Werner syndrome protein regulate neuronal plasticity

btjuang@nctu.edu.tw (Bi-Tzen Juang) — Mon, 01 Mar 2021 00:00:00 +0000

Caenorhabditis elegans expresses human Werner syndrome protein (WRN) orthologs as two distinct proteins: MUT-7, with a 3'-5' exonuclease domain, and CeWRN-1, with helicase domains. How these domains cooperate remains unclear. Here, we demonstrate the different contributions of MUT-7 and CeWRN-1 to 22G small interfering RNA (siRNA) synthesis and the plasticity of neuronal signaling. MUT-7 acts specifically in the cytoplasm to promote siRNA biogenesis and in the nucleus to associate with CeWRN-1. The import of siRNA by the nuclear Argonaute NRDE-3 promotes the loading of the heterochromatin-binding protein HP1 homolog HPL-2 onto specific loci. This heterochromatin complex represses the gene expression of the guanylyl cyclase ODR-1 to direct olfactory plasticity in C. elegans. Our findings suggest that the exonuclease and helicase domains of human WRN may act in concert to promote RNA-dependent loading into a heterochromatin complex, and the failure of this entire process reduces plasticity in postmitotic neurons.

Parathyroid hormone attenuates osteoarthritis pain by remodeling subchondral bone in mice

xcao11@jhmi.edu (Gehua Zhen) — Mon, 01 Mar 2021 00:00:00 +0000

Osteoarthritis, a highly prevalent degenerative joint disorder, is characterized by joint pain and disability. Available treatments fail to modify osteoarthritis progression and decrease joint pain effectively. Here, we show that intermittent parathyroid hormone (iPTH) attenuates osteoarthritis pain by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration in a destabilized medial meniscus (DMM) mouse model. We found that subchondral sensory innervation for osteoarthritis pain was significantly decreased in PTH-treated DMM mice compared with vehicle-treated DMM mice. In parallel, deterioration of subchondral bone microarchitecture in DMM mice was attenuated by iPTH treatment. Increased level of prostaglandin E2 in subchondral bone of DMM mice was reduced by iPTH treatment. Furthermore, uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling was regulated by PTH-induced endocytosis of the PTH type 1 receptor–transforming growth factor β type 2 receptor complex. Notably, iPTH improved subchondral bone microarchitecture, and decreased level of prostaglandin E2 and sensory innervation of subchondral bone in DMM mice by acting specifically through PTH type 1 receptor in Nestin⁺ mesenchymal stromal cells. Thus, iPTH could be a potential disease-modifying therapy for osteoarthritis.

Latrophilin GPCR signaling mediates synapse formation

richard.sando@vanderbilt.edu (Richard Sando) — Mon, 01 Mar 2021 00:00:00 +0000

Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.