Biology subjects

Wei, X.

Publications and source records attributed to Wei, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

Age-Related Changes of Dopamine D1 and D2 Receptors Expression in Parvalbumin-Positive Cells of the Orbitofrontal and Prelimbic Cortices of Mice

Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remains unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In both the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes in both regions. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.

neuroscience↗

bioRxiv2023

Lithocholic acid targets TULP3 to activate sirtuins and AMPK to retard ageing

Lithocholic acid (LCA), accumulated in the body during calorie restriction (CR), can confer administered metazoans with the ability to activate AMP-activated protein kinase (AMPK) and retard ageing. However, how LCA is signalled to activate AMPK and elicit the biological effects is unclear. Here, we show that LCA can enhance sirtuins (SIRTs) to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), thereby triggering AMPK activation via the lysosomal glucose-sensing pathway. Through proteomic analysis of SIRT1-coimmunoprecipitated proteins, we identify and validate that TUB like protein 3 (TULP3) is a constitutive component of SIRTs. Surprisingly, we found that TULP3 is an LCA receptor, and that the LCA-bound TULP3 activates SIRTs. The activated SIRTs in turn deacetylate the V1E1 subunit of v-ATPase on K52, K99 and K191 residues. Muscle-specific expression of the 3KR mutant of V1E1, mimicking the deacetylated state, dominantly activates AMPK and rejuvenates muscles in aged mice. Moreover, LCA once administered also activates AMPK and extends lifespan and healthspan in nematodes and flies, depending on the TULP3 homologues tub-1 and ktub, respectively. Our study thus elucidates that LCA triggers the TULP3-sirtuin-v-ATPase- AMPK route to manifest benefits of calorie restriction.

physiology↗

bioRxiv2023

Lithocholic acid phenocopies rejuvenating and life-extending effects of calorie restriction

Calorie restriction (CR) is a dietary intervention to promote health and longevity. CR causes various metabolic changes in both the production and circulation of metabolites; however, it remains unclear which of the changed metabolite(s) can account for the physiological benefits of CR. Through metabolomic analysis of metabolites undergoing abundance changes during CR and subsequent functional validation, we found that lithocholic acid (LCA) is the only metabolite that alone can recapitulate the effects of CR, including activation of AMPK and the rejuvenating effects of muscle regeneration, grip strength and running capacity in mice. Interestingly, LCA also activates AMPK and exerts life- and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster, indicating that these animal models are able to transmit the signalling of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes, in nematodes and flies, as well as in mice. Together, we have identified that administration of the CR-upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans, in an AMPK-dependent manner.

physiology↗

bioRxiv2023

A therapeutic small molecule lead enhances γ-oscillations and improves cognition/memory in Alzheimer's disease model mice

Brain rhythms provide the timing and concurrence of brain activity required for linking together neuronal ensembles engaged in specific tasks. In particular, the {gamma}-oscillations (30-120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimers disease (AD). Here we report on a potent brain permeable small molecule, DDL-920 that increases {gamma}-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a new class of therapeutics for AD. As a first in CNS pharmacotherapy, our lead candidate acts as a potent, efficacious, and selective negative allosteric modulator (NAM) of the {gamma}-aminobutyric acid type A receptors (GABAARs) assembled from 1{beta}2{delta} subunits. We identified these receptors through anatomical and pharmacological means to mediate the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of {gamma}-oscillations. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brains endogenous {gamma}-oscillations through enhancing the function of PV+INs.

neuroscience↗

bioRxiv2023

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

cancer biology↗

bioRxiv2023

Chaperone-mediated autophagy is an overlooked pathway for mutant α1 antitrypsin Z degradation

Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSC70 for substrate recognition. In 1-antitrypsin deficiency (AATD), a disease characterized by the hepatic build-up of 1-Antitrypsin Z mutant (ATZ), CMAs role had been unclear. This work demonstrates the critical role that CMA plays in preventing ATZ accumulation; suppressing CMA worsens ATZ accumulation, whilst activating it through chemical stimulation or LAMP2A overexpression promotes ATZ breakdown. Specifically, ATZs 121QELLR125 motif is critical for HSC70 recognition and LAMP2As charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of ATZ. This selective activation of CMA operates independently from other autophagy pathways and alleviate ATZ aggregates caused cellular stress. These findings highlight CMAs critical function in cellular protein quality control of ATZ and place it as a novel target for AATD treatment approaches.

cell biology↗

bioRxiv2023

Bio-Mol:Pretraining Multimodality Bioactivity Profile for Enhancing Small Molecule Property Prediction

Non-optimized pharmacokinetic parameters serve as the primary cause of failure in clinical trials of drugs. Therefore, the successful prediction of pharmacokinetic parameters during the pre-clinical stage is crucial for the success of drug candidates. Conventional methods primarily rely on 2D structural information, while advanced models extend the features to other structural-related information or use advanced computational models to improve prediction accuracy. However, to gain a comprehensive understanding of small molecules, integrating bioactivity profiles with chemical structural information is essential. One significant challenge in this integration is the high proportion of missing values within experimentally validated bioactivity profiles for most small molecules. To address this challenge, we introduce Bio-Mol, an artificial intelligence model designed to effectively handle this issue. Bio-Mol utilizes a pretrain and finetune strategy, enabling the incorporation of a large proportion of missing bioactivity profiles during the small molecule representation learning process. Comprehensive evaluations of Bio-Mol demonstrate a notable improvement in predicting molecule properties. The integration of missing bioactivity profiles enhances the AUROC of average 5.2% compared to the previous state-of-the-art models predictions. Furthermore, we explore the potential of Bio-Mol in predicting synergistic drug combinations, highlighting its versatility and broader applications in the field of drug discovery. The successful implementation of Bio-Mol showcases its efficacy in over-coming the challenges posed by missing bioactivity profile data. This model paves the way for optimizing small molecule pharmacokinetics prediction, providing valuable insights for drug development and discovery processes.

bioinformatics↗

bioRxiv2023

Population genetic analyses of longitudinal vaginal microbiome reveal racioethnic evolutionary dynamics and prevailing positive selection of Lactobacillus adhesins

The vaginal microbiome is important for reproductive health and should constantly evolve in response to dynamic host-microbe interactions. The composition of the vaginal microbiome is associated with ethnicity; however, the evolutionary landscape of the vaginal microbiome, especially in the multi-ethnic context, remains under-studied. In this study, we performed a longitudinal evolutionary vaginal microbiome analysis of 351 samples from 35 pregnant women with diverse ethnic backgrounds and validated the main findings in two cohorts totaling 462 samples from 90 multi-ethnic women. Microbiome alpha diversity and community states showed strong ethnic signatures. Lactobacillaceae species had a significantly higher nonsynonymous/synonymous mutation ratio (pN/pS) than non-Lactobacillaceae species in all ethnicities. In addition, non-Lactobacillaceae anaerobic bacteria were enriched in Black and Latino women, with significantly elevated nucleotide diversity and lower pN/pS in Black women. Intriguingly, the Lactobacillaceae species had a large repertoire of positively selected genes, including the human mucin-binding and bacterial cell wall anchor genes, which showed independent, recurrent signatures of positive selection across multiple strains, indicating that the host-microbiome interactions directly drive microbial evolution at the molecular interface. Finally, we propose that the evolutionary metrics reflect the environmental niches of adapting microbes. Our study revealed the extensive ethnic signatures in vaginal microbial diversity, composition, community state, and evolutionary dynamics at species and gene levels, highlighting the importance of studying the host-microbiome ecosystem from an evolutionary perspective. HighlightsO_LIExtensive ethnic signatures in the vaginal microbial diversity, composition, community state, and evolutionary dynamics were demonstrated. C_LIO_LIHealthy Lactobacillaceae species showed lower nucleotide diversity but much more relaxed or even positive selection of genes than non-Lactobacillaceae species. C_LIO_LIIn Black women, non-Lactobacillaceae species displayed higher nucleotide diversity and more stringent negative selection. C_LIO_LILactobacillus mucin-binding and cell wall anchor genes showed convergent signatures of positive selection across vaginal microbiomes. C_LI

microbiology↗

bioRxiv2023

PRIME-BSPre: A genome-wide protein-RNA binding sites prediction method based on templates

Identification of RNA binding sites that potentially interact with RNA-binding proteins facilitates a comprehensive analysis of protein-RNA interactions and enables further investigation into the mechanisms underlying RNA splicing and modification. However, the current experimental data remains limited in comparison to the vast family of RBPs, and deep learning prediction methods are inadequate for those RBPs lacking sufficient interaction data for training. Therefore, we present PRIME-BSPre, a genome-wide method for predicting protein-RNA binding sites based on templates that incorporate both RNA sequence and secondary structure as well as the tertiary structure of corresponding RBPs. We have successfully benchmarked our method on the human genome, demonstrating excellent prediction performance on RBP datasets beyond our library and robustness across cell lines. Additionally, we are pioneers in introducing the low Shannon entropy algorithm to describe binding preferences of RNA motifs. Our predicted results further support the hypothesis that RBPs preferentially bind RNA motifs with low complexity.

bioinformatics↗

bioRxiv2023

Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19

Post-acute sequelae of SARS-CoV-2 infection (PASC) represents an urgent public health challenge, with its impact resonating in over 60 million individuals globally. While a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood studies, with few focusing on samples derived from post-COVID affected tissues. Further, clinical studies alone often provide correlative insights rather than causal relationships. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to truly understand the etiology of PASC. In this study, we have made comprehensive comparisons between bronchoalveolar lavage fluid (BAL) single-cell RNA sequencing (scRNAseq) data derived from clinical PASC samples and relevant PASC mouse models. This revealed a strong pro-fibrotic monocyte-derived macrophage response in respiratory PASC (R-PASC) in both humans and mice, and abnormal interactions between pulmonary macrophages and respiratory resident T cells. IFN-{gamma} emerged as a key node mediating the immune anomalies in R-PASC. Strikingly, neutralizing IFN-{gamma} post the resolution of acute infection reduced lung inflammation, tissue fibrosis, and improved pulmonary gas-exchange function in two mouse models of R-PASC. Our study underscores the importance of performing comparative analysis to understand the root cause of PASC for developing effective therapies.

immunology↗

bioRxiv2023

Progressive community, biogeochemical and evolutionary remodeling of the soil microbiome underpins long-term desert ecosystem restoration

Ecological restoration of degraded lands is essential to human sustainability. Yet, an in-depth community, functional, and evolutionary microbial perspective of long-term restoration of damaged ecosystems is lacking. Herein, we comprehensively assessed the impact of long-term (up to 17 years) restoration of Tengger Desert, China, by multi-omic profiling of 1,910 topsoil samples. The soil biophysiochemical properties, especially soil hydraulics, microbiome stability, and functional diversity, significantly improved during restoration. The soil microbiome transitioned from an extreme oligotrophic and autotrophic community to a diverse copiotrophic ecosystem. The soil microbiota, including fungi, could mediate the soil physicochemical changes through metabolites. Importantly, the systematic rewiring of nutrient cycles featured the multi-domain preference of an efficient carbon fixation strategy in the extreme desert environment. Finally, the microbiome was evolving via positive selections of genes of biogeochemical cycles, resistance, and motility. In summary, we present a comprehensive community, functional, biogeochemical, and evolutionary landscape of the soil microbiome during the long-term restoration of desert environments. We highlight the crucial microbial role in restoration from soil hydraulic and biogeochemical perspectives, offering promising field applications. HighlightsO_LIThe desert soil microbiome transformed from simple oligotrophic to a diverse, stable, and nutrient-rich ecosystem with expanded functional diversity. C_LIO_LIRestoration led to systematically rewired biogeochemical cycles, which are highly efficient in carbon fixation in the desert environment. C_LIO_LIThe microbiome was evolving via positive selections of genes involved in biogeochemical cycles and environmental adaptations. C_LIO_LIMicrobes and metabolites could facilitate desert restoration from hydraulic and biogeochemical aspects, offering promising field applications. C_LI

microbiology↗

bioRxiv2023

Inferring cell trajectories of spatial transcriptomics via optimal transport analysis

The integration of cell transcriptomics and spatial coordinates to organize differentiation trajectories remains a challenge. Here we introduce spaTrack, a trajectory inference method using optimal transport to incorporate both transcriptomics and distance of spatial transcriptomics sequencing data into transition costs. spaTrack could construct fine spatial trajectories reflecting the true differentiation topology, as well as trace cell dynamics across multiple samples with temporal intervals. To capture the dynamic drivers, spaTrack models the cell fate as a function of expression profile along temporal intervals driven by transcription factors. Applying spaTrack, we successfully disentangle spatiotemporal trajectories of axolotl telencephalon regeneration and mouse midbrain development. Furthermore, we uncover diverse malignant lineages expanding in a primary tumor. One of the lineages with upregulated extracellular matrix organization implants to the metastatic site and subsequently colonizes to a secondary tumor. Overall, spaTrack greatly facilitates trajectory inference from spatial transcriptomics, providing insights in cell differentiation of broad areas.

bioinformatics↗

bioRxiv2023

Rapid turnover of centromeric DNA reveals signatures of genetic conflict in Drosophila

Centromeres reside in rapidly evolving, repeat-rich genomic regions, despite their essential function in chromosome segregation. Across organisms, centromeres are rich in selfish genetic elements such as transposable elements and satellite DNAs that can bias their transmission through meiosis. However, these elements still need to cooperate at some level and contribute to, or avoid interfering with, centromere function. To gain insight into the balance between conflict and cooperation at centromeric DNA, we take advantage of the close evolutionary relationships within the Drosophila simulans clade - D. simulans, D. sechellia, and D. mauritiana - and their relative, D. melanogaster. Using chromatin profiling combined with high resolution fluorescence in situ hybridization on stretched DNA, we characterize all centromeres across these species. We discovered dramatic centromere reorganization involving recurrent shifts between retroelements and satellite DNAs over short evolutionary timescales. We also reveal the recent origin (<240 Kya) of telocentric chromosomes in D. sechellia, where the X and 4th centromeres now sit on telomere-specific retroelements. Finally, the Y chromosome centromeres, which are the only chromosomes that do not experience female meiosis, do not show dynamic cycling between satDNA and TEs. The patterns of rapid centromere turnover in these species are consistent with genetic conflicts in the female germline and have implications for centromeric DNA function and karyotype evolution. Regardless of the evolutionary forces driving this turnover, the rapid reorganization of centromeric sequences over short evolutionary timescales highlights their potential as hotspots for evolutionary innovation.

evolutionary biology↗

bioRxiv2023

Scanning sample-specific miRNA regulation from bulk and single-cell RNA-sequencing data

RNA-sequencing technology provides an effective tool for understanding miRNA regulation in complex human diseases, including cancers. A large number of computational methods have been developed to make use of bulk and single-cell RNA-sequencing data to identify miRNA regulations at the resolution of multiple samples (i.e. group of cells or tissues). However, due to the heterogeneity of individual samples, there is a strong need to infer miRNA regulation specific to individual samples to uncover miRNA regulation at single-sample resolution level. Here, we develop a framework, Scan, for scanning sample-specific miRNA regulation. Since a single network inference method or strategy cannot perform well for all types of new data, Scan incorporates 27 network inference methods and two strategies to infer tissue-specific or cell-specific miRNA regulation from bulk or single-cell RNA-sequencing data. Results on bulk and single-cell RNA-sequencing data demonstrate the effectiveness of Scan in inferring sample-specific miRNA regulation. Moreover, we have found that incorporating priori information of miRNA targets can improve the accuracy of miRNA target prediction. In addition, Scan can contribute to the clustering cells/tissues and construction of cell/tissue correlation networks. Finally, the comparison results have shown that the performance of network inference methods is likely to be data-specific, and selecting optimal network inference methods is required for more accurate prediction of miRNA targets. We have made Scan freely available to the public to help infer sample-specific miRNA regulation for new data, benchmark new network inference methods and deepen the understanding of miRNA regulation at the resolution of individual samples.

bioinformatics↗

bioRxiv2023

Identification of a botulinum neurotoxin-like gene cluster in Bacillus toyonensis

Clostridial neurotoxins, which include botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT) are the most potent toxins known, and are the causative agents of the neuroparalytic diseases, botulism and tetanus. Until recently, the clostridial neurotoxin family was restricted to the genus Clostridium, but members of this protein family have been found in a growing number of non-Clostridium species including Weissella, Enterococcus, and Paraclostridium. Here, we report the bioinformatic identification and analysis of a novel clostridial neurotoxin homolog in a Bacillus toyonensis genome recently deposited into the NCBI Genbank database. This putative toxin shares 26-29% identity with its closest BoNT relatives, suggesting that it is likely a novel BoNT-like toxin. It possesses key functional motifs (e.g., HExxH) indicative of toxin protease activity, contains the four characteristic BoNT domains, and is located in a BoNT-like genomic neighborhood containing the upstream non-toxic non-hemagglutinin (NTNH) gene as well as several P47-related genes. Phylogenetically, the toxin clusters as a divergent member of the recently discovered lineage of BoNT-like toxins that includes BoNT/X, BoNT/En, and the insecticidal PMP1. Genomic analysis of the B. toyonensis isolate CH177 revealed additional virulence factors and toxin genes indicative of potential pathogenicity targeting an unknown host species. The Bacillus toyonensis BoNT-like protein (BTNT) adds to a growing number of non-clostridial BoNT-like toxins, adding further information on the intriguing phylogenetic distribution and evolutionary history of the most potent toxins known.

bioinformatics↗

bioRxiv2023

Sorcin-STAT3-Serpin E1/CCL5 axis can be the trigger of pancreatic cancer-associated new-onset diabetes

A rise in blood glucose is the early warning signs of underlying pancreatic cancer (PC), which could be the externalization of genetic events in PC progression. But there is still a vacancy in the field of mechanism research on pancreatic cancer-associated new-onset diabetes (PCAND). Using siRNA-mediated gene knockdown in vitro, we made MIN6 cells incubated with conditioned media from transfected PC cells, and detected its response. Immunological techniques were used to explore the interaction between sorcin and STAT3. Human cytokine array was performed to explore the inflammatory cytokines downstream of sorcin. In the present study, we have identified a PCAND driver gene SRI. In PC cells, sorcin and STAT3 form a positive feedback loop to enhance the transcription of serpin E1 and CCL5, which can impair nearby islet {beta}-cells, likely by activating the p38 pathway. In 88 biopsies, expression of sorcin was elevated in PC tissues, especially so in PCAND patient samples. Furthermore, clinical-SRI gene combination model can better distinguish PCAND from T2DM, and serpin E1 level is higher in the peripheral blood samples from PCAND than T2DM. Thus, Sorcin could be the key driver in PCAND, and figuring out sorcin-STAT3-serpin E1/CCL5 signaling axis can help us better understand the pathogenesis of PCAND and identify potential biomarkers. Statement of significanceThis study mapped out a novel sorcin-STAT3-Serpin E1/CCL5 signaling axis in pancreatic cancer cells, which explains how early pre-symptomatic pancreatic cancer may coincide with new-onset diabetes in some patients.

cancer biology↗

bioRxiv2023

AMPK targets PDZD8 to trigger carbon source shift to glutamine

The shift of carbon utilisation from glucose to other nutrients is a fundamental metabolic adaptation to cope with the decreased glucose oxidation during fasting or starvation1. AMP-activated protein kinase (AMPK) plays crucial roles in manifesting physiological benefits accompanying glucose starvation or calorie restriction2. However, the underlying mechanisms are unclear. Here, we show that low glucose-induced activation of AMPK plays a decisive role in the shift of carbon utilisation from glucose to glutamine. We demonstrate that endoplasmic reticulum (ER)-localised PDZD8, which we identify to be a new substrate of AMPK, is required for the glucose starvation-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527), and promotes it to interact with and activate the mitochondrial glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis3-5, and as a result the ER-mitochondria contact is strengthened. In vivo, PDZD8 enhances glutaminolysis, and triggers mitohormesis that is required for extension of lifespan and healthspan in Caenorhabditis elegans subjected to glucose starvation or caloric restriction. Muscle-specific re-introduction of wildtype PDZD8, but not the AMPK-unphosphorylable PDZD8-T527A mutant, to PDZD8-/- mice is able to rescue the increase of glutaminolysis, and the rejuvenating effects of caloric restriction in aged mice, including grip strength and running capacity. Together, these findings reveal an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis and executes the anti-ageing effects of calorie restriction by promoting inter-organelle crosstalk between ER and mitochondria.

cell biology↗

bioRxiv2023

A framework for Frizzled-G protein coupling and implications to the Wnt-PCP signaling pathways

The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. Understanding FZD activation mechanism is key to unlock these emerging targets. Here we present the cryo-EM structures of FZD6 and FZD3 which are known to relay non-canonical Wnt-PCP (planar cell polarity) signaling pathways as well as FZD1 in their G protein-coupled (active) and G protein-free (inactive) states, respectively. Comparison of the three inactive/active pairs unveiled a shared activation framework among all ten FZDs. Mutagenesis along with imaging and functional analysis on the human lens epithelial tissues suggested potential crosstalk between G-protein binding and Wnt-PCP signaling pathways. Together, this study provides an integrated understanding of FZD structure and function, and lays the foundation for developing therapeutic modulators to activate or inhibit FZD signaling for a range of disorders including cancers and cataracts.

biochemistry↗