scholarly journals The transcription factor Tfap2e/AP-2ε plays a pivotal role in maintaining the identity of basal vomeronasal sensory neurons

2018 ◽  
Author(s):  
Jennifer M Lin ◽  
Ed Zandro M Taroc ◽  
Jesus A Frias ◽  
Aparna Prasad ◽  
Allison N Catizone ◽  
...  
Keyword(s):  
Transcription Factor ◽  
G Protein ◽  
Sensory Neurons ◽  
Control Cell ◽  
Neuronal Cell ◽  
Vomeronasal Organ ◽  
Cell Types ◽  
Protein Subunit ◽  
Cell Type Specific ◽  
Vomeronasal Sensory Neurons

The identity of individual neuronal cell types is defined by the expression of specific combinations of transcriptional regulators that control cell type-specific genetic programs. The epithelium of the vomeronasal organ of mice contains two major types of vomeronasal sensory neurons (VSNs): 1) the apical VSNs which express vomeronasal 1 receptors (V1r) and the G-protein subunit Gαi2 and; 2) the basal VSNs which express vomeronasal 2 receptors (V2r) and the G-protein subunit Gαo. Both cell types originate from a common pool of progenitors and eventually acquire apical or basal identity through largely unknown mechanisms. The transcription factor AP-2ε, encoded by the Tfap2e gene, plays a role in controlling the development of GABAergic interneurons in the main and accessory olfactory bulb (AOB), moreover AP-2ε has been previously described to be expressed in the VSNs. Here we show that AP-2ε is expressed in postmitotic VSNs after they commit to the basal differentiation program. Loss of AP-2ε function resulted in reduced number of basal VSNs and in an increased number of neurons expressing markers of the apical lineage. Our work suggests that AP-2ε, which is expressed in late phases of differentiation, is not needed to initiate the apical-basal differentiation dichotomy but for maintaining the basal VSNs' identity by preventing the expression of apical genes. Moreover, our data suggest that differentiated VSNs of mice retain a notable level of plasticity.

scholarly journals Central role of G protein Gαi2 and Gαi2+ vomeronasal neurons in balancing territorial and infant-directed aggression of male mice

2019 ◽  
Vol 116 (11) ◽  
pp. 5135-5143 ◽  
Author(s):  
Anne-Charlotte Trouillet ◽  
Matthieu Keller ◽  
Jan Weiss ◽  
Trese Leinders-Zufall ◽  
Lutz Birnbaumer ◽  
...  
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Neural Activity ◽  
Parental Behavior ◽  
Vomeronasal Organ ◽  
Male Infant ◽  
Lateral Septum ◽  
Male Mice ◽  
Protein Subunit ◽  
Α Subunit

Aggression is controlled by the olfactory system in many animal species. In male mice, territorial and infant-directed aggression are tightly regulated by the vomeronasal organ (VNO), but how diverse subsets of sensory neurons convey pheromonal information to limbic centers is not yet known. Here, we employ genetic strategies to show that mouse vomeronasal sensory neurons expressing the G protein subunit Gαi2 regulate male–male and infant-directed aggression through distinct circuit mechanisms. Conditional ablation of Gαi2 enhances male–male aggression and increases neural activity in the medial amygdala (MeA), bed nucleus of the stria terminalis, and lateral septum. By contrast, conditional Gαi2 ablation causes reduced infant-directed aggression and decreased activity in MeA neurons during male–infant interactions. Strikingly, these mice also display enhanced parental behavior and elevated neural activity in the medial preoptic area, whereas sexual behavior remains normal. These results identify Gαi2 as the primary G protein α-subunit mediating the detection of volatile chemosignals in the apical layer of the VNO, and they show that Gαi2+ VSNs and the brain circuits activated by these neurons play a central role in orchestrating and balancing territorial and infant-directed aggression of male mice through bidirectional activation and inhibition of different targets in the limbic system.

scholarly journals Brn-3a suppresses pseudorabies virus-induced cell death in sensory neurons

2007 ◽  
Vol 88 (3) ◽  
pp. 743-747 ◽  
Author(s):  
Kristin Geenen ◽  
Hans J. Nauwynck ◽  
Nick De Regge ◽  
Kevin Braeckmans ◽  
Herman W. Favoreel
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Life Cycle ◽  
Sensory Neurons ◽  
Pseudorabies Virus ◽  
Neuronal Cell ◽  
Cell Types ◽  
Target Cells ◽  
Crucial Importance ◽  
Major Target

Sensory neurons of the trigeminal ganglion (TG) are of crucial importance in the pathogenesis of many alphaherpesviruses, constituting major target cells for latency and reactivation events. We showed earlier that a subpopulation of porcine TG neurons, in contrast to other porcine cell types, is highly resistant to cell death induced by infection with the porcine alphaherpesvirus pseudorabies virus (PRV). Here, we report that expression of Brn-3a, a neuron-specific transcription factor implicated in cell survival of sensory neurons, correlates with the increased resistance of TG neurons towards PRV-induced cell death. In addition, overexpression of Brn-3a in the sensory neuronal cell line ND7 markedly increased resistance of these cells to PRV-induced cell death. Hence, Brn-3a may play a hitherto uncharacterized role in protection of sensory neurons from alphaherpesvirus-induced cell death, which may have implications for different aspects of the alphaherpesvirus life cycle, including latency/reactivation events.

scholarly journals A single cell brain atlas in human Alzheimer’s disease

2019 ◽  
Author(s):  
Alexandra Grubman ◽  
Gabriel Chew ◽  
John F. Ouyang ◽  
Guizhi Sun ◽  
Xin Yi Choo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Single Cell ◽  
Cell Fate ◽  
Expression Patterns ◽  
Cell Types ◽  
Gene Expression Patterns ◽  
Cell Type ◽  
Web Resource ◽  
Cell Type Specific

AbstractAlzheimer’s disease (AD) is a heterogeneous disease that is largely dependent on the complex cellular microenvironment in the brain. This complexity impedes our understanding of how individual cell types contribute to disease progression and outcome. To characterize the molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA- seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting specific cellular contributions to global gene expression patterns between control and Alzheimer’s patient brains. We observed distinct cellular regulation of APOE which was repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD subclusters show discordant expression of APOE. Integration of transcription factor regulatory modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under the control of transcription factor EB (TFEB), a master regulator of lysosomal function and which initiated a regulatory cascade containing multiple AD GWAS genes. These results establish functional links between specific cellular sub-populations in AD, and provide new insights into the coordinated control of AD GWAS genes and their cell-type specific contribution to disease susceptibility. Finally, we created an interactive reference web resource which will facilitate brain and AD researchers to explore the molecular architecture of subtype and AD-specific cell identity, molecular and functional diversity at the single cell level.HighlightsWe generated the first human single cell transcriptome in AD patient brainsOur study unveiled 9 clusters of cell-type specific and common gene expression patterns between control and AD brains, including clusters of genes that present properties of different cell types (i.e. astrocytes and oligodendrocytes)Our analyses also uncovered functionally specialized sub-cellular clusters: 5 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological gene categoriesOur analyses found manifold AD GWAS genes specifically associated with one cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated between different brain cell-types in AD sub-cellular clustersWe mapped the regulatory landscape driving transcriptional changes in AD brain, and identified transcription factor networks which we predict to control cell fate transitions between control and AD sub-cellular clustersFinally, we provide an interactive web-resource that allows the user to further visualise and interrogate our dataset.Data resource web interface:http://adsn.ddnetbio.com

scholarly journals Complexity and graded regulation of neuronal cell-type–specific alternative splicing revealed by single-cell RNA sequencing

2021 ◽  
Vol 118 (10) ◽  
pp. e2013056118
Author(s):  
Huijuan Feng ◽  
Daniel F. Moakley ◽  
Shuonan Chen ◽  
Melissa G. McKenzie ◽  
Vilas Menon ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Single Cell ◽  
Neuronal Cell ◽  
Cell Types ◽  
Gabaergic Neurons ◽  
Cell Type ◽  
Differential Splicing ◽  
Single Cell Rna Sequencing ◽  
Hierarchical Levels ◽  
Cell Type Specific

The enormous cellular diversity in the mammalian brain, which is highly prototypical and organized in a hierarchical manner, is dictated by cell-type–specific gene-regulatory programs at the molecular level. Although prevalent in the brain, the contribution of alternative splicing (AS) to the molecular diversity across neuronal cell types is just starting to emerge. Here, we systematically investigated AS regulation across over 100 transcriptomically defined neuronal types of the adult mouse cortex using deep single-cell RNA-sequencing data. We found distinct splicing programs between glutamatergic and GABAergic neurons and between subclasses within each neuronal class. These programs consist of overlapping sets of alternative exons showing differential splicing at multiple hierarchical levels. Using an integrative approach, our analysis suggests that RNA-binding proteins (RBPs) Celf1/2, Mbnl2, and Khdrbs3 are preferentially expressed and more active in glutamatergic neurons, while Elavl2 and Qk are preferentially expressed and more active in GABAergic neurons. Importantly, these and additional RBPs also contribute to differential splicing between neuronal subclasses at multiple hierarchical levels, and some RBPs contribute to splicing dynamics that do not conform to the hierarchical structure defined by the transcriptional profiles. Thus, our results suggest graded regulation of AS across neuronal cell types, which may provide a molecular mechanism to specify neuronal identity and function that are orthogonal to established classifications based on transcriptional regulation.

scholarly journals Olfactory and Vomeronasal Receptor Feedback Employ Divergent Mechanisms of PERK Activation

2018 ◽  
Author(s):  
Ryan P Dalton ◽  
G Elif Karagöz ◽  
Jerome Kahiapo ◽  
Ruchira Sharma ◽  
Lisa E Bashkirova ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Sensory Neurons ◽  
Olfactory Receptor ◽  
Vomeronasal Receptor ◽  
Gene Regulatory ◽  
Lumenal Domain ◽  
Vomeronasal Sensory Neurons

AbstractMutually-exclusive chemoreceptor expression in olfactory and vomeronasal sensory neurons (OSNs and VSNs) enables odorant discrimination. This configuration involves chemoreceptor mediated activation of the endoplasmic reticulum (ER)-resident kinase PERK. PERK drives translation of the transcription factor ATF5 to preclude additional chemoreceptor expression. ATF5 translation is transient in OSNs but persistent in VSNs, suggesting chemoreceptor-specific modes of PERK activation. Herein, we showed that the ER-lumenal domain (LD) of PERK recognized vomeronasal receptor (VR)-derived peptides, suggesting direct PERK activation drives persistent ATF5 translation in VSNs. In contrast, PERK LD did not recognize olfactory receptor (OR)-derived peptides in vitro, and facilitating OR maturation in vivo prevented PERK activation, suggesting that ORs activate PERK indirectly through a failure to exit the ER. Importantly, impairing or prolonging ATF5 expression drove specific chemoreceptor repertoire biases. Together, these results demonstrate mechanistic divergence in chemoreceptor feedback and establish that differences in PERK activation promote qualitatively different gene regulatory results.

scholarly journals Cell type-specific biotin labeling in vivo resolves regional neuronal proteomic differences in mouse brain

2021 ◽  
Author(s):  
Sruti Rayaprolu ◽  
Sara Bitarafan ◽  
Ranjita Betarbet ◽  
Sydney N Sunna ◽  
Lihong Cheng ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Neurological Diseases ◽  
Neuronal Cell ◽  
Cell Types ◽  
Proteomic Profiling ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific ◽  
The Brain

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

scholarly journals Super-enhancers are transcriptionally more active and cell-type-specific than stretch enhancers

2018 ◽  
Author(s):  
Aziz Khan ◽  
Anthony Mathelier ◽  
Xuegong Zhang
Keyword(s):  
Control Cell ◽  
Cell Types ◽  
Small Subset ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Regulatory Regions ◽  
Cell Identity ◽  
Transcription Start Sites ◽  
Numerous Cell ◽  
Cell Type Specific

AbstractBackgroundSuper-enhancers and stretch enhancers represent classes of transcriptional enhancers that have been shown to control the expression of cell identity genes and carry disease- and trait-associated variants. Specifically, super-enhancers are clusters of enhancers defined based on the binding occupancy of master transcription factors (TFs), chromatin regulators, or chromatin marks, while stretch enhancers are large chromatin-defined regulatory regions of at least 3,000 base pairs. Several studies have characterized these regulatory regions in numerous cell types and tissues to decipher their functional importance. However, the differences and similarities between these regulatory regions have not been fully assessed.ResultsWe integrated genomic, epigenomic, and transcriptomic data from ten human cell types to perform a comparative analysis of super and stretch enhancers with respect to their chromatin profiles, cell-type-specificity, and ability to control gene expression. We found that stretch enhancers are more abundant, more distal to transcription start sites, cover twice as much the genome and are significantly less conserved than super-enhancers. In contrast, super-enhancers are significantly more enriched for active chromatin marks and cohesin complex and transcriptionally active than stretch enhancers. Importantly, a vast majority of superenhancers (85%) overlap with only a small subset of stretch enhancers (13%), which are enriched for cell-type-specific biological functions, and control cell identity genes.ConclusionsThese results suggest that super-enhancers are transcriptionally more active and cell-type-specific than stretch enhancers, and importantly, most of the stretch enhancers that are distinct from superenhancers do not show an association with cell identity genes, are less active, and more likely to be poised enhancers.

scholarly journals Single nucleus analysis of the chromatin landscape in mouse forebrain development

2017 ◽  
Author(s):  
Sebastian Preissl ◽  
Rongxin Fang ◽  
Yuan Zhao ◽  
Ramya Raviram ◽  
Yanxiao Zhang ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Regulatory Sequences ◽  
Specific Cell ◽  
Cell Type ◽  
Tissue Samples ◽  
Forebrain Development ◽  
Cell Type Specific ◽  
Accessible Chromatin

ABSTRACTGenome-wide analysis of chromatin accessibility in primary tissues has uncovered millions of candidate regulatory sequences in the human and mouse genomes1–4. However, the heterogeneity of biological samples used in previous studies has prevented a precise understanding of the dynamic chromatin landscape in specific cell types. Here, we show that analysis of the transposase-accessible-chromatin in single nuclei isolated from frozen tissue samples can resolve cellular heterogeneity and delineate transcriptional regulatory sequences in the constituent cell types. Our strategy is based on a combinatorial barcoding assisted single cell assay for transposase-accessible chromatin5 and is optimized for nuclei from flash-frozen primary tissue samples (snATAC-seq). We used this method to examine the mouse forebrain at seven development stages and in adults. From snATAC-seq profiles of more than 15,000 high quality nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell-types in foetal and adult forebrains. We further define cell-type specific cis regulatory sequences and infer potential master transcriptional regulators of each cell population. Our results demonstrate the feasibility of a general approach for identifying cell-type-specific cis regulatory sequences in heterogeneous tissue samples, and provide a rich resource for understanding forebrain development in mammals.

An autoradiographic analysis of the development of the chick trigeminal ganglion

Development ◽  
1980 ◽  
Vol 55 (1) ◽  
pp. 167-182
Author(s):  
Adele D'Amico-Martel ◽  
Drew M. Noden
Keyword(s):  
Neural Crest ◽  
Sensory Neurons ◽  
Trigeminal Ganglion ◽  
Neuronal Cell ◽  
Cell Types ◽  
Dark Neurons ◽  
Immature Neurons ◽  
Autoradiographic Analysis ◽  
The Times ◽  
Unique Relationship

The avian trigeminal ganglion, which is embryonically derived from the neural crest and epidermal placodes, consists of two topographically segregated classes of immature neurons, large and small, during the second week of incubation, and two neuronal cell types, dark and light, interspersed throughout the mature ganglion. In order to establish the times of terminal mitosis of trigeminal sensory neurons, embryos were treated with [3H]thymidine during the first week of incubation and their ganglia fixed on embryonic day 11. The embryonically large, distal, placodal-derived neurons are generated between days 2 and 5, while the small, proximal, neural crest-derived neurons are formed mostly between days 4 and 7. By comparing the locations of labeled cells in ganglia treated with isotope but fixed on day 18 of incubation with their 11-day counterparts, we have proved that there are no morphogenetic rearrangements of neurons during the final week of incubation. Thus, no unique relationship exists between the two neuron types in the mature ganglion and the two cell classes in the immature trigeminal. Therefore, both the light and the dark neurons in the mature trigeminal ganglion arise from neural crest as well as placodal primordia.

Cell-cell interactions modulate the responsiveness of PC12 cells to nerve growth factor

Development ◽  
1987 ◽  
Vol 101 (3) ◽  
pp. 605-615
Author(s):  
P. Doherty ◽  
D.A. Mann ◽  
F.S. Walsh
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Pc12 Cells ◽  
Neuronal Cell ◽  
Cell Types ◽  
Glioma Cell Line ◽  
Protein Subunit ◽  
Neurofilament Protein ◽  
Nerve Growth ◽  
Cell Cell

The growth of PC12 cells on a collagen substratum or on monolayers of several non-neuronal cell types was studied by measuring nerve growth factor (NGF)-dependent increases in the expression of a 150 X 10(3) (Mr) neurofilament protein subunit and the membrane glycoprotein Thy-1. Both responses were found to be greatly suppressed in cultures of fibroblasts as compared to the C2 and G8-1 muscle cell lines and the C6 glioma cell line. This suppression was associated with an inhibition of NGF-dependent neuritic outgrowth from PC12 cells grown on fibroblast monolayers. There was no evidence that fibroblasts secrete soluble molecules that directly inhibit these responses or neutralize NGF. In addition, there was no difference in the neurofilament protein response from PC12 cells that had been treated with NGF prior to coculture, and the now primed PC12 cells readily extended axons over fibroblast monolayers. These data demonstrate that cell-cell and/or cell-matrix interactions can modulate biochemical responses to NGF and suggest that responsiveness of neuronal cells to environmental cues is not immutable. Control of the latter may be at the level of expression of receptor molecules for cell-surface- or matrix-associated macromolecules and a similar mechanism operating during development could play a role in growth cone guidance.

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