PLoS Biology最新文献

{"title":"Melanocortin 1 receptor mediates melanin production by interacting with the BBSome in primary cilia.","authors":"Xiaoyu Tian, Hanyu Wang, Song Liu, Wei Liu, Kaiyue Zhang, Xiaohan Gao, Qingchao Li, Huijie Zhao, Liangran Zhang, Peiwei Liu, Min Liu, Youjun Wang, Xueliang Zhu, Rutao Cui, Jun Zhou","doi":"10.1371/journal.pbio.3002940","DOIUrl":"10.1371/journal.pbio.3002940","url":null,"abstract":"<p><p>Production of melanin pigments is a protective mechanism of the skin against ultraviolet (UV)-induced damage and carcinogenesis. However, the molecular basis for melanogenesis is still poorly understood. Herein, we demonstrate a critical interplay between the primary cilium and the melanocortin 1 receptor (MC1R) signaling. Our data show that UV and α-melanocyte-stimulating hormone (α-MSH) trigger cilium formation in human melanocytes and melanoma cells. Deficiency of MC1R or the presence of its red hair color (RHC) variations significantly attenuates the UV/α-MSH-induced ciliogenesis. Further investigation reveals that MC1R enters the cilium upon UV/α-MSH stimulation, which is facilitated by the interaction of MC1R with the BBSome and the palmitoylation of MC1R. MC1R interacts with the BBSome through the second and third intercellular loops, which contain the common RHC variant alleles (R151C and R160W). These RHC variants of MC1R exhibit attenuated ciliary localization, and enforced ciliary localization of these variants elevates melanogenesis. Ciliary MC1R triggers a sustained cAMP signaling and selectively stimulates Sox9, which appears to up-regulate melanogenesis-related genes as the transcriptional cofactor for MITF. These findings reveal a previously unrecognized nexus between MC1R and cilia and suggest an important mechanism for RHC variant-related pigmentary defects.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002940"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-analysis of single-cell RNA sequencing co-expression in human neural organoids reveals their high variability in recapitulating primary tissue.","authors":"Jonathan M Werner, Jesse Gillis","doi":"10.1371/journal.pbio.3002912","DOIUrl":"10.1371/journal.pbio.3002912","url":null,"abstract":"<p><p>Human neural organoids offer an exciting opportunity for studying inaccessible human-specific brain development; however, it remains unclear how precisely organoids recapitulate fetal/primary tissue biology. We characterize field-wide replicability and biological fidelity through a meta-analysis of single-cell RNA-sequencing data for first and second trimester human primary brain (2.95 million cells, 51 data sets) and neural organoids (1.59 million cells, 173 data sets). We quantify the degree primary tissue cell type marker expression and co-expression are recapitulated in organoids across 10 different protocol types. By quantifying gene-level preservation of primary tissue co-expression, we show neural organoids lie on a spectrum ranging from virtually no signal to co-expression indistinguishable from primary tissue, demonstrating a high degree of variability in biological fidelity among organoid systems. Our preserved co-expression framework provides cell type-specific measures of fidelity applicable to diverse neural organoids, offering a powerful tool for uncovering unifying axes of variation across heterogeneous neural organoid experiments.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002912"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The thalamus encodes and updates context representations during hierarchical cognitive control.","authors":"Xitong Chen, Stephanie C Leach, Juniper Hollis, Dillan Cellier, Kai Hwang","doi":"10.1371/journal.pbio.3002937","DOIUrl":"10.1371/journal.pbio.3002937","url":null,"abstract":"<p><p>Cognitive flexibility relies on hierarchically structured task representations that organize task contexts, relevant environmental features, and subordinate decisions. Despite ongoing interest in the human thalamus, its role in cognitive control has been understudied. This study explored thalamic representation and thalamocortical interactions that contribute to hierarchical cognitive control in humans. We found that several thalamic nuclei, including the anterior, mediodorsal, ventrolateral, and pulvinar nuclei, exhibited stronger evoked responses when subjects switch between task contexts. Decoding analysis revealed that thalamic activity encodes task contexts within the hierarchical task representations. To determine how thalamocortical interactions contribute to task representations, we developed a thalamocortical functional interaction model to predict task-related cortical representation. This data-driven model outperformed comparison models, particularly in predicting activity patterns in cortical regions that encode context representations. Collectively, our findings highlight the significant contribution of thalamic activity and thalamocortical interactions for contextually guided hierarchical cognitive control.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002937"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Axons compensate for biophysical constraints of variable size to uniformize their action potentials.","authors":"János Brunner, Antónia Arszovszki, Gergely Tarcsay, János Szabadics","doi":"10.1371/journal.pbio.3002929","DOIUrl":"10.1371/journal.pbio.3002929","url":null,"abstract":"<p><p>Active conductances tune the kinetics of axonal action potentials (APs) to support specialized functions of neuron types. However, the temporal characteristics of voltage signals strongly depend on the size of neuronal structures, as capacitive and resistive effects slow down voltage discharges in the membranes of small elements. Axonal action potentials are particularly sensitive to these inherent biophysical effects because of the large diameter variabilities within individual axons, potentially implying bouton size-dependent synaptic effects. However, using direct patch-clamp recordings and voltage imaging in small hippocampal axons in acute slices from rat brains, we demonstrate that AP shapes remain uniform within the same axons, even across an order of magnitude difference in caliber. Our results show that smaller axonal structures have more Kv1 potassium channels that locally re-accelerate AP repolarization and contribute to size-independent APs, while they do not preclude the plasticity of AP shapes. Thus, size-independent axonal APs ensure consistent digital signals for each synapse within axons of same types.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002929"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temperature cues are integrated in a flexible circadian neuropeptidergic feedback circuit to remodel sleep-wake patterns in flies.","authors":"Xin Yuan, Hailiang Li, Fang Guo","doi":"10.1371/journal.pbio.3002918","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002918","url":null,"abstract":"<p><p>Organisms detect temperature signals through peripheral neurons, which relay them to central circadian networks to drive adaptive behaviors. Despite recent advances in Drosophila research, how circadian circuits integrate temperature cues with circadian signals to regulate sleep/wake patterns remains unclear. In this study, we used the FlyWire brain electron microscopy connectome to map neuronal connections, identifying lateral posterior neurons LPNs as key nodes for integrating temperature information into the circadian network. LPNs receive input from both circadian and temperature-sensing neurons, promoting sleep behavior. Through connectome analysis, genetic manipulation, and behavioral assays, we demonstrated that LPNs, downstream of thermo-sensitive anterior cells (ACs), suppress activity-promoting lateral dorsal neurons LNds via the AstC pathway, inducing sleep Disrupting LPN-LNd communication through either AstCR1 RNAi in LNds or in an AstCR1 mutant significantly impairs the heat-induced reduction in the evening activity peak. Conversely, optogenetic calcium imaging and behavioral assays revealed that cold-activated LNds subsequently stimulate LPNs through NPF-NPFR signaling, establishing a negative feedback loop. This feedback mechanism limits LNd activation to appropriate levels, thereby fine-tuning the evening peak increase at lower temperatures. In conclusion, our study constructed a comprehensive connectome centered on LPNs and identified a novel peptidergic circadian feedback circuit that coordinates temperature and circadian signals, offering new insights into the regulation of sleep patterns in Drosophila.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002918"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intracellular polarization of RNAs and proteins in the human small intestinal epithelium.","authors":"Roy Novoselsky, Yotam Harnik, Oran Yakubovsky, Corine Katina, Yishai Levin, Keren Bahar Halpern, Niv Pencovich, Ido Nachmany, Shalev Itzkovitz","doi":"10.1371/journal.pbio.3002942","DOIUrl":"10.1371/journal.pbio.3002942","url":null,"abstract":"<p><p>The intestinal epithelium is a polarized monolayer of cells, with an apical side facing the lumen and a basal side facing the blood stream. In mice, both proteins and mRNAs have been shown to exhibit global basal-apical polarization; however, polarization in the human intestine has not been systematically explored. Here, we employed laser-capture microdissection to isolate apical and basal epithelial segments from intestinal tissues of 8 individuals and performed RNA sequencing and mass-spectrometry proteomics. We find a substantial polarization of mRNA molecules that largely overlaps polarization patterns observed in mice. This mRNA polarization remains consistent across different zones of the intestinal villi and is generally correlated with the polarization of proteins. Our protein analysis exposes streamlined intracellular nutrient transport and processing and reveals that mitochondria and ribosomes are less polarized in humans compared to mice. Our study provides a resource for understanding human intestinal epithelial biology.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002942"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A chromosomal mutation is superior to a plasmid-encoded mutation for plasmid fitness cost compensation.","authors":"Rosanna C T Wright, A Jamie Wood, Michael J Bottery, Katie J Muddiman, Steve Paterson, Ellie Harrison, Michael A Brockhurst, James P J Hall","doi":"10.1371/journal.pbio.3002926","DOIUrl":"10.1371/journal.pbio.3002926","url":null,"abstract":"<p><p>Plasmids are important vectors of horizontal gene transfer in microbial communities but can impose a burden on the bacteria that carry them. Such plasmid fitness costs are thought to arise principally from conflicts between chromosomal- and plasmid-encoded molecular machineries, and thus can be ameliorated by compensatory mutations (CMs) that reduce or resolve the underlying causes. CMs can arise on plasmids (i.e., plaCM) or on chromosomes (i.e., chrCM), with contrasting predicted effects upon plasmid success and subsequent gene transfer because plaCM can also reduce fitness costs in plasmid recipients, whereas chrCM can potentially ameliorate multiple distinct plasmids. Here, we develop theory and a novel experimental system to directly compare the ecological effects of plaCM and chrCM that arose during evolution experiments between Pseudomonas fluorescens SBW25 and its sympatric mercury resistance megaplasmid pQBR57. We show that while plaCM was predicted to succeed under a broader range of parameters in mathematical models, chrCM dominated in our experiments, including conditions with numerous recipients, due to a more efficacious mechanism of compensation, and advantages arising from transmission of costly plasmids to competitors (plasmid \"weaponisation\"). We show analytically the presence of a mixed Rock-Paper-Scissors (RPS) regime for CMs, driven by trade-offs with horizontal transmission, that offers one possible explanation for the observed failure of plaCM to dominate even in competition against an uncompensated plasmid. Our results reveal broader implications of plasmid-bacterial evolution for plasmid ecology, demonstrating the importance of specific compensatory mutations for resistance gene spread. One consequence of the superiority of chrCM over plaCM is the likely emergence in microbial communities of compensated bacteria that can act as \"hubs\" for plasmid accumulation and dissemination.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 12","pages":"e3002926"},"PeriodicalIF":9.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Making sense of cilia: The role of intraflagellar transport.","authors":"Renny Ng, Chih-Ying Su","doi":"10.1371/journal.pbio.3002924","DOIUrl":"10.1371/journal.pbio.3002924","url":null,"abstract":"<p><p>Intraflagellar transport (IFT) is essential for both ciliary structure and function. A new study in PLOS Biology reveals how IFT-mediated trafficking and ciliary morphology differentially influence chemosensory responses between neuronal types and among co-expressed receptors.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 11","pages":"e3002924"},"PeriodicalIF":9.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated vesicular Zn2+ in dorsal root ganglion neurons expressing the transporter TMEM163 causes age-associated itchy skin in mice.","authors":"Fang Tong, Shuai Liu, Chen Zhang, Xicheng Gu, Huan Yang, Bin Zhou, Yun-Yun Wang, Jianwei Chen, Qianhui Qu, Ye Gong, Haili Pan, Chen Liang, Changlin Li, Xin Zhang, Qingjian Han","doi":"10.1371/journal.pbio.3002888","DOIUrl":"10.1371/journal.pbio.3002888","url":null,"abstract":"<p><p>The prevalent itching condition associated with aging, historically referred to as senile pruritus, diminishes quality of life. Despite its impact, effective treatments remain elusive, largely due to an incomplete understanding of its pathological cause. In this study, we reveal a subset of dorsal root ganglion neurons enriched with Zn2+ that express the vesicular Zn2+ transporter TMEM163. These neurons form direct synapses with and modulate the activity of spinal NPY+ inhibitory interneurons. In aged mice, both the expression of TMEM163 and the concentration of vesicular Zn2+ within the central terminals of TMEM163+ primary afferents show marked elevation. Importantly, the excessive release of vesicular Zn2+ significantly dampens the activity of NPY+ neurons, triggering the disinhibition of itch-transmitting neural circuits and resulting in chronic itch. Intriguingly, chelating Zn2+ within the spinal dorsal horn effectively relieves itch in aged mice. Our study thus unveils a novel molecular mechanism underlying senile pruritus.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 11","pages":"e3002888"},"PeriodicalIF":9.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cilia structure and intraflagellar transport differentially regulate sensory response dynamics within and between C. elegans chemosensory neurons.","authors":"Alison Philbrook, Michael P O'Donnell, Laura Grunenkovaite, Piali Sengupta","doi":"10.1371/journal.pbio.3002892","DOIUrl":"10.1371/journal.pbio.3002892","url":null,"abstract":"<p><p>Sensory neurons contain morphologically diverse primary cilia that are built by intraflagellar transport (IFT) and house sensory signaling molecules. Since both ciliary structural and signaling proteins are trafficked via IFT, it has been challenging to decouple the contributions of IFT and cilia structure to neuronal responses. By acutely inhibiting IFT without altering cilia structure and vice versa, here we describe the differential roles of ciliary trafficking and sensory ending morphology in shaping chemosensory responses in Caenorhabditis elegans. We show that a minimum cilium length but not continuous IFT is necessary for a subset of responses in the ASH nociceptive neurons. In contrast, neither cilia nor continuous IFT are necessary for odorant responses in the AWA olfactory neurons. Instead, continuous IFT differentially modulates response dynamics in AWA. Upon acute inhibition of IFT, cilia-destined odorant receptors are shunted to ectopic branches emanating from the AWA cilia base. Spatial segregation of receptors in these branches from a cilia-restricted regulatory kinase results in odorant desensitization defects, highlighting the importance of precise organization of signaling molecules at sensory endings in regulating response dynamics. We also find that adaptation of AWA responses upon repeated exposure to an odorant is mediated by IFT-driven removal of its cognate receptor, whereas adaptation to a second odorant is regulated via IFT-independent mechanisms. Our results reveal unexpected complexity in the contribution of IFT and cilia organization to the regulation of responses even within a single chemosensory neuron type and establish a critical role for these processes in the precise modulation of olfactory behaviors.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"22 11","pages":"e3002892"},"PeriodicalIF":9.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11593760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142733128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}