查看更多>>摘要：Dendritic morphology is typically highly branched,and the branching and synaptic abundance of dendrites can enhance the receptive range of neurons and the diversity of information received,thus providing the basis for information processing in the nervous system.Once dendritic development is aberrantly compromised or damaged,it may lead to abnormal connectivity of the neural network,affecting the function and stability of the nervous system and ultimately triggering a series of neurological disorders.Research on the regulation of dendritic developmental processes has flourished,and much progress is now being made in its regulatory mechanisms.Noteworthily,dendrites are characterized by an extremely complex dendritic arborization that cannot be attributed to individual protein functions alone,requiring a systematic analysis of the intrinsic and extrinsic signals and the coordinated roles among them.Actin cytoskeleton organization and membrane vesicle trafficking are required during dendrite development,with actin providing tracks for vesicles and vesicle trafficking in turn providing material for actin assembly.In this review,we focus on these two basic biological processes and discuss the molecular mechanisms and their synergistic effects underlying the morphogenesis of neuronal dendrites.We also offer insights and discuss strategies for the potential preventive and therapeutic treatment of neuropsychiatric disorders.
查看更多>>摘要：Gene therapy has shown significant potential in treating various diseases,particularly inherited blood disorders such as hemophilia,sickle cell disease,and thalassemia.Advances in understanding the regu-latory network of disease-associated genes have led to the identification of additional therapeutic targets for treatment,especially for β-hemoglobinopathies.Erythroid regulatory factor BCL11A offers the most promising therapeutic target for β-hemoglobinopathies,and reduction of its expression using the commercialized gene therapy product Casgevy has been approved for use in the UK and USA in 2023.Notably,the emergence of innovative gene editing technologies has further broadened the gene therapy landscape,presenting possibilities for treatment.Intensive studies indicate that base editing and prime editing,built upon CRISPR technology,enable precise single-base modification in hematopoietic stem cells for addressing inherited blood disorders ex vivo and in vivo.In this review,we present an overview of the current landscape of gene therapies,focusing on clinical research and gene therapy products for inherited blood disorders,evaluation of potential gene targets,and the gene editing tools employed in current gene therapy practices,which provides an insight for the establishment of safer and more effective gene therapy methods for a wider range of diseases in the future.
查看更多>>摘要：More and more studies have demonstrated that pseudogenes possess coding ability,and the functions of their transcripts in the development of diseases have been partially revealed.However,the role of pseu-dogenes in maintenance of normal physiological states and life activities has long been neglected.Here,we identify pseudogenes that are dynamically expressed during human early embryogenesis,showing different expression patterns from that of adult tissues.We explore the expression correlation between pseudo-genes and the parent genes,partly due to their shared gene regulatory elements or the potential regulation network between them.The essential role of three pseudogenes,PI4KAP1,TMED10P1,and FBXW4P1,in maintaining self-renewal of human embryonic stem cells is demonstrated.We further find that the three pseudogenes might perform their regulatory functions by binding to proteins or microRNAs.The pseudogene-related single-nucleotide polymorphisms are significantly associated with human congenital disease,further illustrating their importance during early embryonic development.Overall,this study is an excavation and exploration of functional pseudogenes during early human embryonic development,sug-gesting that pseudogenes are not only capable of being specifically activated in pathological states,but also play crucial roles in the maintenance of normal physiological states.
查看更多>>摘要：Zebrafish embryos possess two major types of myofibers,the slow and fast fibers,with distinct patterns of cell fusion.The fast muscle cells can fuse,while the slow muscle cells cannot.Here,we show that myo-maker is expressed in both slow and fast muscle precursors,whereas myomixer is exclusive to fast muscle cells.The loss of Prdm1a,a regulator of slow muscle differentiation,results in strong myomaker and myomixer expression and slow muscle cell fusion.This abnormal fusion is further confirmed by the direct ectopic expression of myomaker or myomixer in slow muscle cells of transgenic models.Using the transgenic models,we show that the heterologous fusion between slow and fast muscle cells can alter slow muscle cell migration and gene expression.Furthermore,the overexpression of myomaker and myomixer also disrupts membrane integrity,resulting in muscle cell death.Collectively,this study identifies that the fiber-type-specific expression of fusogenic proteins is critical for preventing inappropriate fusion between slow and fast fibers in fish embryos,highlighting the need for precise regulation of fusogenic gene expression to maintain muscle fiber integrity and specificity.
查看更多>>摘要：Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547deIC,p.(Arg183Alafs*186)and c.605G＞A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmental delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse model expressing the R183Afs and W202X mutations.We report that the Ntng2R183Afs/W202X mice exhibit hypo-tonia and impaired learning and memory.We find that the levels of CaMKⅡ and p-GluA1Ser831 are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKⅡ,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKⅡ agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2 deficiency leads to impairments of cognitive ability and synaptic plasticity.
查看更多>>摘要：Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to or-gans.Recently,the Cingulin(CGN)protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant non-syndromic hearing loss.Here,we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death.Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice,resembling the auditory phenotype in human patients.Interestingly,a human-specific residue(V1112)in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN.Moreover,the expression of heat shock factor 1(HSF1)decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death.In summary,these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN,which can be targeted by the expression of the cell chaperone response regulator HSF1.
查看更多>>摘要：Human UDP-glycosyltransferases(UGTs)are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs.Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk.However,the genetic complexity beyond these variants has not been comprehensively assessed.We here leveraged whole-exome and whole-genome sequencing data from 141,456 unrelated individuals across 7 major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family.Overall,9666 exonic variants were observed,of which 98.9％were rare.To interpret the functional impact of UGT missense variants,we developed a gene family-specific variant effect predictor.This algorithm identified a total of 1208 deleterious variants,most of which were found in African and South Asian pop-ulations.Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites.Combined,our analyses provide a systematic overview of UGT variability,which can yield insights into interindividual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.
查看更多>>摘要：Nicotine is widely recognized as the primary contributor to tobacco dependence.Previous studies have indicated that molecular and behavioral responses to nicotine are primarily mediated by ventral tegmental area(VTA)neurons,and accumulating evidence suggests that glia play prominent roles in nicotine addiction.However,VTA neurons and glia have yet to be characterized at the transcriptional level during the progression of nicotine self-administration.Here,a male mouse model of nicotine self-administration is established and the timing of three critical phases(pre-addiction,addicting,and post-addiction phase)is characterized.Single-nucleus RNA sequencing in the VTA at each phase is performed to comprehensively classify specific cell subtypes.Adaptive changes occurred during the addicting and post-addiction phases,with the addicting phase displaying highly dynamic neuroplasticity that profoundly impacts the transcription in each cell subtype.Furthermore,significant transcriptional changes in energy metabolism-related genes are observed,accompanied by notable structural alterations in neuronal mitochondria during the pro-gression of nicotine self-administration.The results provide insights into mechanisms underlying the pro-gression of nicotine addiction,serving as an important resource for identifying potential molecular targets for nicotine cessation.
查看更多>>摘要：Cold stress in low-temperature environments can trigger changes in gene expression,but epigenomics regulation of temperature stability in vital tissues,including the fat and diencephalon,is still unclear.Here,we explore the cold-induced changes in epigenomic features in the diencephalon and fat tissues of two cold-resistant Chinese pig breeds,Min and Enshi black(ES)pigs,utilizing H3K27ac CUT&Tag,RNA-seq,and selective signature analysis.Our results show significant alterations in H3K27ac modifications in the diencephalon of Min pigs and the fat of ES pigs after cold exposure.Dramatic changes in H3K27ac modifications in the diencephalon of Min pig are primarily associated with genes involved in energy metabolism and hormone regulation,whereas those in the fat of ES pig are primarily associated with immunity-related genes.Moreover,transcription factors PRDM1 and HSF1,which show evidence of se-lection,are enriched in genomic regions presenting cold-responsive alterations in H3K27ac modification in the Min pig diencephalon and ES pig fat,respectively.Our results indicate the diversity of epigenomic response mechanisms to cold exposure between Min and ES pigs,providing unique epigenetic resources for studies of low-temperature adaptation in large mammals.
查看更多>>摘要：Avian ovaries develop asymmetrically apart from prey birds,with only the left ovary growing more towards functional organ.Here,we analyze over 135,000 cells from chick's left and right ovaries at six distinct embryonic developmental stages utilizing single-cell transcriptome sequencing.We delineate gene expression patterns across 15 cell types within these embryo ovaries,revealing side-specific development.The left ovaries exhibit cortex cells,zygotene germ cells,and transcriptional changes unique to the left side.Differential gene expression analysis further identifies specific markers and pathways active in these cell types,highlighting the asymmetry in ovarian development.A fine-scale analysis of the germ cell meiotic transcriptome reveals seven distinct clusters with gene expression patterns specific to various meiotic stages.The study also identifies signaling pathways and intercellular communications,particularly between pre-granulosa and germ cells.Spatial transcriptome analysis shows the asymmetry,demonstrating cortex cells exclusively in the left ovary,modulating neighboring cell types through putative secreted signaling molecules.Overall,this single-cell analysis provides insights into the molecular mechanisms of the asymmetric development of avian ovaries,particularly the significant role of cortex cells in the left ovary.
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维普