Single-cell profiling and functional characterization bridge molecular and functional features of NAc neuron subtype
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PROVIDER: PRJNA484018 | ENA |
REPOSITORIES: ENA
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Project description:The functional complexity of nucleus accumbens (NAc) has been extensively characterized in recent years. However, the molecular and cellular heterogeneity beyond the established D1 and D2 medium spiny neuron (MSN) subtypes, which likely underlie its diverse functions, are not well understand. Here, we present the cell taxonomy of mouse NAc generated from single-cell transcriptomic profiling, which not only reveals a rich cellular heterogeneity within both NAc MSN and interneuron populations, but also identified tight correlation between the transcriptional feature and spatial distribution of NAc neuron subtypes, supporting the notion that functional heterogeneity of NAc sub-regions can arises from differential distribution of molecularly distinct neuronal populations. To further test this idea, we focused on a D1 MSN subtype identified from our analysis and demonstrated that these cells possess distinct anatomic location, neural connection and more importantly, behavioral function. Collectively, our work not only created comprehensive cell taxonomy of NAc, but also provided insights into how functional heterogeneity is embedded in this brain region.
2021-08-24 | GSE118020 | GEO
Project description:Pyramidal neuron subtype diversity governs microglia states in the neocortex [MERFISH]
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Project description:In this study, NAC was UV-crosslinked using the photo-crosslinking amino acid p-benzoyl-L-phenylalanine (pBPA) in order to determine specific interaction sites of the alphaNAC N-terminus in the native protein structure. Furthermore, quantitative chemical crosslinking coupled to mass spectrometry (q-XL-MS) was used to compare crosslink abundances of a NAC mutant versus wild type NAC in order to determine the influence of the mutated motive on the structural dynamics of NAC.
2019-07-25 | PXD011995 | Pride
Project description:Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally-distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes, and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily-conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss of prdm16 or mecom causes fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.
2023-08-24 | GSE240026 | GEO
Project description:Determinants of Motor Neuron Functional Subtypes Important for Locomotor Speed
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Project description:Background: Neoadjuvant chemotherapy (NAC) is the standard treatment for muscle-invasive bladder cancer (MIBC), yet 40% of patients progress, emphasizing the need for biomarkers predictive for response or chemoresistance. Gene expression-based subtypes may serve as biomarkers, though which subtypes will respond, notably when it comes to the basal subtype, remains contentious. Patients and methods: This post hoc study analyzed 300 NAC-treated patients enrolled in the GETUG/AFU VESPER trial, with transurethral diagnostic formalin-fixed paraffin-embedded which underwent pathological review before being sequenced. ‘Mixed’ subtype was defined for tumors displaying at least two different Consensus molecular subtypes in separate regions. We evaluated the association between molecular subtypes and outcome after NAC. Tumors with remaining tissue at cystectomy (n ¼ 83) were compared with pre-treatment tumors. Results: Cases were classified basal/squamous (Ba/Sq) (n ¼ 84), luminal unstable (n = 57), stroma-rich (n = 53), mixed (n = 48), luminal papillary (n ¼ 39), luminal non-specific (n = 18), and neuroendocrine-like (n ¼ 1), with 30/48 mixed cases including a Ba/Sq component. Compared with other molecular subtypes in a multivariate Cox model, Ba/Sq (pure or mixed) patients had an increased hazard ratio (HR) of progression-free survival [HR 2.0, 95% confidence interval (CI) 1.36-3.0]. Mixed tumors were associated with decreased metabolic activity that could account for chemoresistance. Ba/Sq and mixed non-responders mostly maintained their subtype at cystectomy and have fewer myeloid dendritic cells after NAC. Tumors classified luminal papillary at transurethral resection of the urinary bladder tumor exhibited an increase in T CD4þ and macrophage signatures after NAC. Other subtypes did not show significant immune changes after NAC. Our study design relied on detailed pathological review, which precluded evaluating the mixed subtype in published datasets. Furthermore, the sample size for post-NAC analyses constrained the statistical power of these findings. Conclusions: Our findings underscore the importance of recognizing intra-tumor heterogeneity in MIBC and its role in chemoresistance associated with Ba/Sq subtype, and provide valuable insights that could help future treatment development and improve patient outcomes.
2024-10-19 | GSE279390 | GEO
Project description:Microglia are the resident immune cells of the brain, and have critical roles in circuit development and plasticity. During embryonic and postnatal development, microglia exist in multiple transcriptional states. However, it is still poorly understood how these states are established, and whether they are influenced by their cellular environment. Here we show that in the juvenile neocortex, microglia exist in multiple states whose identity and laminar distribution is instructed by the neuronal class identity of local pyramidal neurons. Using single-cell RNA sequencing, we unveil molecular signatures of distinct microglia sub-states, and show that they can be divided into layer-restricted or broadly-distributed states. Strikingly, conversion of deep-layer pyramidal neurons to an alternate class identity reconfigures both the density and molecular state of local layer-restricted microglia to correspond to the new neuronal niche, thus identifying specific populations of microglia that are sensitive to pyramidal neuron subtypes. Ligand-receptor interactomes for individual neuronal subtype-microglia pairings uncovers two categories of neuron-to-microglia communication: one associated with neuronal class identity and one associated with microglial state. Our findings highlight the fundamental role that neuronal identity and neuronal niches play in locally controlling the transcriptional status of postnatal microglia.
2022-04-26 | GSE193760 | GEO
Project description:Alzheimer’s disease (AD), the predominant cause of late-life dementia, has a multifactorial etiology. Since there are few therapeutic options for symptomatic AD, research is increasingly focused on the identification of pre-symptomatic biomarkers. Recently, evaluation of neuron-derived exosomal markers has emerged as a promising novel approach for determining neuronal dysfunction. We aimed to identify novel neuron-derived exosomal markers that signify a transition from normal aging to Mild Cognitive Impairment (MCI) and then to clinically established AD, a sequence we refer to as AD progression. By using a Tandem Mass Tag-based quantitative proteomic approach, we identified a total of 360 neuron-derived exosomal proteins. Subsequent fuzzy c-means clustering revealed two clusters of proteins displaying trends of gradually increasing/decreasing expression over the period of AD progression (normal to MCI to AD), both of which were mainly involved in immune response-associated pathways, proteins within these clusters were defined as bridge proteins. Several differentially expressed proteins (DEPs) were identified in the progression of AD. The intersections of bridge proteins and DEPs were defined as key proteins, including C7 (Complement component 7), FERMT3 (Fermitin Family Member 3), CAP1 (Adenylyl cyclase-associated protein 1), ENO1 (Enolase 1) and ZYX (Zyxin), among which the expression patterns of C7 and ZYX were almost consistent with the proteomic results. Collectively, we propose that C7 and ZYX might be two novel neuron-derived exosomal protein markers, expression of which might be used to evaluate cognitive decline before a clinical diagnosis of AD is warranted.
2022-02-17 | PXD027561 | Pride
Project description:A pliable mediator acts as a functional, rather than an architectural bridge, between promoters and enhancers
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Project description:Investigate whole genome gene expression level changes in an S. flexneri ntrBC and nac mutants compared to wild type strain. NtrBC is a two component regulatory system, nac is a transcriptional activator Mutations in ntrBC and nac result in small plaque formation in Henle cell monolayers compared to wild type bacteria. Gene expression studies were pursued to identify the genes regulated by these transcriptional regulators. A 9 array study using total RNA recovered from the wild type, ntrBC and nac mutant strains in three independent experiments. Bacterial RNA was isolated from infected Henle cells at four hours post-infection. Gene expression from the mutant strains was compared to that of wild type.
2014-05-09 | E-GEOD-49939 | biostudies-arrayexpress