Biology subjects

Wang, L.-Y.

Publications and source records attributed to Wang, L.-Y..

17 recordsLinked to original sources

bioRxiv2026

Evolutionary and multi-omic divergences associated with the extreme sexual size dimorphism in spiders

Extreme sexual size dimorphism (SSD) represents one of the most striking forms of phenotypic divergence between the sexes, yet the genomic basis of extreme body-size dimorphism remains poorly understood. Orb-weaving spiders exhibit some of the most pronounced female-biased SSD among terrestrial arthropods, providing an exceptional system for investigating the evolutionary and genomic changes associated with extreme SSD. Here, we combined comparative genomics across 51 spider species with sex-resolved transcriptomic and chromatin profiling in the highly dimorphic Joro spider, Trichonephila clavata. Across spiders, we identified SSD-associated evolutionary-rate shifts in genes involved in chromatin regulation, growth, and cuticle structural organization. We further found a significant positive association between JHAMT copy number and SSD, with larger gene repertoires occurring in more extremely dimorphic lineages. In T. clavata, expanded JHAMT paralogs showed sex- and tissue-biased expression together with sex-specific differences in chromatin accessibility and local chromatin interactions. Integrated multi-omic analyses further revealed coordinated sex-specific differences in transcription, chromatin accessibility, and chromatin interactions across genes involved in ecdysteroid signaling, insulin and growth regulation, and epidermal and cuticular processes. Altogether, these findings provide insight into the evolutionary and regulatory changes associated with extreme female-biased SSD in spiders.

zoology↗

bioRxiv2026

Calcium-dependent facilitation of P/Q-type calcium channels governs the polarity and magnitude of short-term synaptic plasticity

P/Q-type calcium channel (Cav2.1) is the major channel that mediates Ca2+ influx during action potentials (APs) and evokes neurotransmitter release from presynaptic terminals. Repetitive activity induces its Ca2+-dependent facilitation (CDF) via binding of calmodulin (CaM) superfamily proteins to the IQ-like motif, specifically isoleucine (I) and methionine (M) sites, on the cytoplasmic c-terminus of Cav2.1. However, whether and how CDF contributes to short-term synaptic plasticity remains elusive. By recordings from the calyx of Held terminal in IQ-like motif point mutation knock-in mice (Cav2.1 IM-AA KI), we found that activity-dependent CDF is completely abolished, resulting in lower quantal output and shorter release time course as well as profound reductions in the magnitute of short-term facilitation and depression (STF and STD) in different Ca2+ concentrations. Prolonging deactivation of Ca2+ channels by broadening spike width normalizes quantal output and release time course in Cav2.1 IM-AA synapses, but does not fully rescue STF/STD. These results indicate that CDF of Cav2.1 channels governs the polarity and magnitude of short-term synaptic plasticity in fast-spiking central synapses.

neuroscience↗

bioRxiv2025

Genomic signatures associated with convergent funnel-web building behavior in spiders

Spiders exhibited diverse and intricate web-building behaviors, which represent a classic model for studying the evolution of complex traits. The funnel-web, a sheet-like web with a retreat tube, has evolved independently in several spider lineages, especially in the families Agelenidae and Macrothelidae. This repeated emergence of a complex behavior offers an example of this funnel-web building behavioral convergence. Here, we present a chromosome-level genome assembly of the agelenid spider Tamgrinia laticeps, along with annotated genomes of another agelenid spider Eratigena atrica, and a macrothelid Orientothele yani which convergently evolved funnel-web building behavior. Comparative genomic analysis of 15 spider species with diverse web-types revealed convergent signatures associated with funnel-web construction. Hundreds of genes tended to experience convergent shift in selective pressure, convergent positive section, and harbored convergent amino acid substitutions. These genes are associated with synaptic transmission (e.g., SLC6A3, Gabbr1, SNAP25), neuromuscular coordination (e.g., ine, VAChT), and behavioral regulation (e.g., Crtc1, Lrrc7). Notably, we detected identical convergent amino acid changes in VAChT and ine across all three funnel-web builders. Our findings demonstrate that convergent evolution of web architecture is linked to nervous system evolution, providing genomic insights into the basis of behavioral convergence.

genomics↗

bioRxiv2025

ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation

Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including neural precursor hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

N1 cassette-lacking NMDA receptors mediate the antidepressant activity of ketamine

Ketamine has emerged as a rapid-acting and robust antidepressant1,2. However, the mechanism of its antidepressant action remains enigmatic. The core issue that has yet to be resolved is whether NMDA receptors (NMDARs), which are subject to open channel blockade by ketamine3,4, mediate the antidepressant effect. NMDARs naturally undergo alternative splicing of the obligatory GluN1 subunit5, producing receptor diversity in the brain that has not been considered in the actions of ketamine. Here we discover that alternative splicing of Grin1 exon 5, which leads to exclusion (GluN1a) or inclusion (GluN1b) of the N1 cassette, located in the N-terminal domain of GluN1 distant from the pore, unexpectedly dictates the level and dynamics of NMDAR blockade by ketamine and gates its antidepressant activity. We find that ketamine prevents NMDAR-dependent long-term potentiation (LTP) in the CA1 region of the hippocampus in mice engineered to exclude Grin1 exon 5 (GluN1a mice), but ketamine has no effect on LTP in mice engineered to include this exon (GluN1b mice). Ketamine inhibits synaptic NMDARs in CA1 pyramidal neurons in both GluN1a and GluN1b mice, with the level of steady-state blockade marginally greater in GluN1a- than in GluN1b-containing NMDARs. However, the rate of relief of ketamine blockade upon membrane depolarization is markedly slower in GluN1a than in GluN1b neurons such that GluN1a-containing receptors remain blocked during bursting activity, whereas those containing GluN1b escape the ketamine blockade. Furthermore, ketamine treatment, either via systemic administration or local infusion into the hippocampus, induces an antidepressant effect in GluN1a mice but has no effect in GluN1b mice. Collectively, we identify GluN1a-containing NMDARs, which are persistently blocked by ketamine during neuronal firing activity, to be selectively responsible for the antidepressant effect.

neuroscience↗

bioRxiv2024

Disease-linked mutations dysregulate neuronal condensate physical properties, composition, and RNA translation

Local RNA translation is essential for development. In neurons, deficient local translation linked with mutations in scaffold proteins results in dysregulated dendrite and dendritic spine growth. However, mechanisms by which these proteins control translation and how disease-linked mutations induce aberrant translation were unclear. We use biochemical reconstitution and neuronal assays to show that mutations to the neuronal condensate scaffold shank2 cause physical hardening and altered composition of condensates; a key RNA translation-modulator FMRP is excluded from mutant condensates. Functionally, shank2 condensates repress translation while condensates composed of shank2 with intrinsically disordered region-localized missense mutations promote translation. These results demonstrate that disease-linked dysregulation of condensate physical properties and composition is an underlying mechanism of aberrant RNA translation often observed in disease. One Sentence SummaryDisease-linked missense mutations in the postsynaptic density scaffold protein shank2 dysregulate phase separated biomolecular condensate physical properties and composition resulting in aberrant RNA translation.

biophysics↗

bioRxiv2024

Hijacking a dedicated entorhinal-hippocampal extinction circuit to remove traumatic memory

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells suffice fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhances the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD shows potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be hijacked for therapy to remove traumatic memory trace. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/593830v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@ca6768org.highwire.dtl.DTLVardef@4ae574org.highwire.dtl.DTLVardef@11e4ff5org.highwire.dtl.DTLVardef@1136cc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Neuropeptide Y co-opts neuronal ensembles for memory lability and stability

Memory engrams are formed by activity-dependent recruitment of distinct subsets of excitatory principal neurons (or neuronal ensembles) whereas inhibitory neurons pivot memory lability and stability1-5. However, the molecular logic for memory engrams to preferentially recruit specific type of interneurons over other subtypes remains enigmatic. Using activity-dependent single-cell transcriptomic profiling6-8 in mice with training of cued fear memory and extinction, we discovered that neuropeptide Y (NPY)-expressing (NPY+) GABAergic interneurons in the ventral hippocampal CA1 (vCA1) region exert fast GABAergic inhibition to facilitate the acquisition of memory, but bifurcate NPY-mediated slow peptidergic inhibition onto distinct sub-ensembles underlying the extinction of single memory trace. Genetically encoded calcium and NPY sensors revealed that both calcium dynamics of NPY+ neurons and their NPY release in vCA1 ramp up as extinction learning progresses while behavioral state switches from "fear-on" to "fear-off". Bidirectional manipulations of NPY+ neurons or NPY itself demonstrated NPY is both necessary and sufficient to control the rate and degree of memory extinction by acting on two physically non-overlapping sub-ensembles composed of NPY1R- and NPY2R-expressing neurons. CRISPR/Cas9-mediated knockout of NPY2R or NPY1R further unravels that NPY co-opts its actions on these two sub-ensembles to gate early fast and late slow stages of extinction. These findings exemplify the intricate spatiotemporal orchestration of slow peptidergic inhibitions from single subtype of GABAergic interneurons to fine-tune engram lability verse stability of memory.

neuroscience↗

bioRxiv2024

High resolution cryo-EM of V-ATPase in native synaptic vesicles

Neurotransmitter release into the synaptic cleft between neurons enables the intercellular communication central to the function of the brain. In the presynaptic neuron, the proton pumping vesicular- or vacuolar-type ATPase (V-ATPase) powers neurotransmitter loading into synaptic vesicles (SVs), with the V1 complex dissociating from the membrane region of the enzyme before exocytosis. We isolated SVs from rat brain using SidK, a V-ATPase-binding bacterial effector protein. Single particle electron cryomicroscopy of the vesicles allowed high-resolution structure determination of V-ATPase within the native SV membrane. In the structure, regularly spaced cholesterol molecules decorate the enzymes rotor and the abundant SV protein synaptophysin binds the complex stoichiometrically. Conditions where ATP hydrolysis drives glutamate loading result in loss of V1 from the SV membrane, suggesting that SV loading is sufficient to induce V-ATPase dissociation.

biochemistry↗

bioRxiv2024

Glutamate as a co-agonist for acid-sensing ion channels to aggravate ischemic brain damage

Glutamate is traditionally viewed as the first messenger to activate N-methyl-D-aspartate receptors (NMDARs) and downstream cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other NMDAR-independent mechanisms3-7. Here we show that glutamate and its structural analogs, including NMDAR antagonist L-AP5 (or APV), robustly potentiated currents mediated by acid-sensing ion channels (ASICs) which are known for driving acidosis-induced neurotoxicity in stroke4. Glutamate increased the proton affinity and open probability of ASICs, aggravating ischemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis and structure-based in silico molecular docking and simulations uncovered a novel glutamate binding cavity in the extracellular domain of ASIC1a. Computational drug screening of NMDAR competitive antagonist analogs identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs, providing strong neuroprotection efficacy comparable to that in ASIC1a or other cation ion channel knockout mouse models4-7. We conclude that glutamate serves as the first messenger for ASICs to exacerbate neurotoxicity, and that selective blockage of glutamate binding sites on ASICs without affecting NMDARs may be of strategic importance for developing effective stroke therapeutics devoid of the psychotic side effects of NMDAR antagonists.

neuroscience↗

bioRxiv2024

Relaxed selection and horizontal gene transfer fuel underwater adaptation in a water spider

Spiders have primarily adapted to terrestrial life, yet a number of species have made evolutionary transitions to marine and freshwater environments. While its physiological and behavioral adaptations have been characterized, the genetic basis of semi-aquatic and aquatic adaptation in spiders remains poorly understood. Here, we provide a high-quality, chromosome-level genome assembly for the aquatic spider Argyroneta aquatica, alongside a reference transcriptome for the semi-aquatic spider Desis martensi. We performed comparative genomes analyses of 22 spider species, including a unique aquatic spider, two semi-aquatic spiders and 19 terrestrial spider species, with a focus on those in the marronoid clade. By integrating morphological, phylogenomic, comparative genomic, transcriptomic, and metabolomic analyses, we explored the genomic adaptations of aquatic and semi-aquatic spiders. Phylogenomic analysis suggests that aquatic and semi-aquatic spiders have independently evolved from their terrestrial ancestors and represent divergent evolutionary routes We found hundreds of genes tend to experience relaxed selection, positive selection, and evidence of horizontal gene transfer (HGT) associated with the transition to aquatic and semi-aquatic life in spiders. These genes are associated with respiratory, osmoregulatory, fat metabolism and digestion, hypoxia, and thermal functions, putatively facilitate the adaptations to diverse underwater life. Altogether, our findings highlight the divergent evolutionary mechanisms enabling spiders to thrive in diverse aquatic environments, providing insights into the genomic basis of adaptations to semi-aquatic and aquatic habitats.

genomics↗

bioRxiv2023

Detrimental Impact of a Type VI Secretion System on Direct Interspecies Electron Transfer

Direct interspecies electron transfer (DIET) is important in anaerobic communities of environmental and practical significance. Other than the need for close physical contact for electrical connections, the interactions of DIET partners are poorly understood. Type VI secretion systems (T6SSs) typically kill competitive microbes. Surprisingly, Geobacter metallireducens highly expressed T6SS genes when DIET-based co-cultures were initiated with Geobacter sulfurreducens. T6SS gene expression was lower when the electron shuttle anthraquinone-2,6-disulfonate was added to alleviate the need for interspecies contact. Disruption of hcp, the G. metallireducens gene for the main T6SS needle-tube protein subunit, and the most highly upregulated gene in DIET-grown cells, eliminated the long lag periods required for the initiation of DIET. The mutation did not aid DIET in the presence of granular activated carbon, consistent with the fact that DIET partners do not make physical contact when electrically connected through conductive materials. The hcp-deficient mutant also established DIET quicker with Methanosarcina barkeri. However, the mutant also reduced Fe(III) oxide faster than the wild-type strain, a phenotype not expected from the loss of the T6SS. Quantitative PCR revealed greater gene transcript abundance for key components of extracellular electron transfer in the hcp-deficient mutant versus the wild-type strain, potentially accounting for the faster Fe(III) oxide reduction and impact on DIET. The results highlight that interspecies interactions beyond electrical connections may influence DIET effectiveness. The unexpected increase in the expression of genes for extracellular electron transport components when hcp was deleted emphasize the complexities in evaluating the electromicrobiology of highly adaptable Geobacter species. IMPORTANCEDirect interspecies electron transfer (DIET) is an alternative to the much more intensively studied process of interspecies H2 transfer as a mechanism for microbes to share electrons during the cooperative metabolism of energy sources. DIET is an important process in anaerobic soils and sediments generating methane, a significant greenhouse gas. Facilitating DIET can accelerate and stabilize the conversion of organic wastes to methane biofuel in anaerobic digesters. Therefore, a better understanding of the factors controlling how fast DIET partnerships are established is expected to lead to new strategies for promoting this bioenergy process. The finding that when co-cultured with G. sulfurreducens, G. metallireducens initially expressed a type VI secretion system, a behavior not conducive to interspecies cooperation, illustrates the complexity in establishing syntrophic relationships.

microbiology↗

bioRxiv2022

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

neuroscience↗

bioRxiv2021

Conservation and divergence of poly(A) tail regulation during the mammalian oocyte-to-embryo transition

Poly(A) tail length and non-A residues are vital for oocyte-to-embryo transition (OET) in mice and humans1-5. However, the role of poly(A) tail length and non-A residues during OET in other commonly used mammalian animal models for human diseases remains unexplored. In addition, the degree of conservation in maternal mRNA poly(A) tail dynamics during OET across different mammal species is unknown. Here, we conduct a comparative analysis of the poly(A) tails during OET across four species: mice, rats, pigs, and humans. Dynamics during OET found to be conserved across all four species include: maternal mRNA deadenylation during oocyte maturation and re-polyadenylation after fertilization; a fall-rise trend in poly(A) tail length distribution; a rise-fall trend in the ratio of poly(A) tails with non-A residues; higher abundance of non-A residues in poly(A) tails of maternal mRNA than in zygotic genome activation (ZGA) mRNA; maternal mRNA with U residues degrades faster than those without U residues at the stage when ZGA takes place. While in mice and rats maternal mRNA deadenylation is impaired in parthenogenetic embryos and ZGA inhibition leads to blocked maternal mRNA deadenylation in mice and humans. In contrast, the length of consecutive U residues and the duration time of U residues in poly(A) tail diverges across the four species. Together, these findings reveal that the poly(A) tail mediated maternal mRNA post-transcriptional regulation is highly conserved in mammals with unique divergences in the length and life-span of U residues, providing new insights for the further understanding of OET across different mammals.

developmental biology↗

bioRxiv2021

Abundant non-A residues in the poly(A) tail orchestrate the mouse oocyte-to-embryo transition

Non-A (U, G, and C) residues can be added to the 5-end, internal, and 3-end positions of poly(A) tails of RNA transcripts1-3, and some of these have been shown to regulate mRNA stability4, 5. The mammalian oocyte-to-embryo transition (OET) relies on post-transcriptional regulation of maternal RNA, because transcription is silent during this process until the point of zygotic genome activation (ZGA)6-9. Although the regulation of mRNA translation by poly(A) tail length plays an important role in the mammalian OET, the dynamics and functions of non-A residues in poly(A) tails are completely unknown. In this study, we profiled the genome-wide presence, abundance, and roles of non-A residues during the OET in mice using PAIso-seq1 and PAIso-seq22, 10, two complementary methods of poly(A) tail analysis. We found that non-A residues are highly dynamic in maternal mRNA, following a general pattern of beginning to increase at the MII stage, becoming highly abundant after fertilization with U residues in about half of poly(A) tails in 1-cell embryos, and declining in 2-cell embryos. We revealed that Btg4-mediated global maternal mRNA deadenylation created the substrates for U residue addition by Tut4/7 at their 3-ends and further re-polyadenylation. In addition, G residues can be added by Tent4a/b. Finally, we demonstrate that G residues stabilize the modified mRNA, while the U residues mark maternal RNA for faster degradation in 2-cell mouse embryos. Taken together, these findings demonstrate that non-A residues are abundant and re-sculpt the maternal transcriptome to initiate zygotic development, which reveals the functional importance of the post-transcriptional regulation mediated by non-A residues in mRNA poly(A) tails.

developmental biology↗

bioRxiv2019

Targeting of RBM10 to S1-1 Nuclear Bodies: Targeting Sequences and its Biological Significance

RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, revealed that RBM10 possesses two S1-1 NB-targeting sequences (NBTSs), one in the KEKE motif region and another in the C2H2 Zn finger (ZnF). These NBTSs act synergistically to localize RBM10 to S1-1 NBs. The C2H2 ZnF not only acts as an NBTS, but is also essential for AS regulation by RBM10. Moreover, RBM10 does not participate in S1-1 NB formation, and without alterations of RBM10 protein levels, its NB-localization changes, increasing as cellular transcriptional activity declines, and vice versa. These results indicate that RBM10 is a transient component of S1-1 NBs and is sequestered in NBs via its NBTSs when cellular transcription decreases. We propose that the C2H2 ZnF exerts its NB-targeting activity when RBM10 is unbound by pre-mRNAs, and that NB-localization of RBM10 is a mechanism to control its AS activity in the nucleus. Note that the previous title of this manuscript was Targeting of RBM10 to S1-1 Nuclear Bodies: Targeting Sequences and its Biological Significance.

molecular biology↗

bioRxiv2017

Potential for Methanosarcina to contribute to uranium reduction during acetate-promoted groundwater bioremediation

Previous studies of in situ bioremediation of uranium-contaminated groundwater with acetate injections have focused on the role of Geobacter species in U(VI) reduction because of a lack of other abundant known U(VI)-reducing microorganisms. Monitoring the levels of methyl CoM reductase subunit A (mcrA) transcripts during an acetate-injection field experiment demonstrated that acetoclastic methanogens from the genus Methanosarcina were enriched after 40 days of acetate amendment. The increased abundance of Methanosarcina corresponded with an accumulation of methane in the groundwater. An enrichment culture dominated by a Methanosarcina species with the same Methanosarcina mcrA sequence that predominated in the field experiment could effectively convert acetate to methane. In order to determine whether Methanosarcina species could be participating in U(VI) reduction in the subsurface, cell suspensions of M. barkeri were incubated in the presence of U(VI) with acetate provided as the electron donor. U(VI) was reduced by metabolically active M. barkeri cells, however, no U(VI) reduction was observed in inactive controls. These results demonstrate that Methanosarcina species could play an important role in the long-term bioremediation of uranium-contaminated aquifers after depletion of Fe(III) oxides limits the growth of Geobacter species. The results also suggest that Methanosarcina have the potential to influence uranium geochemistry in a diversity of anaerobic sedimentary environments.

microbiology↗