1,721,002 research outputs found
Brain-specific microRNAs induce neurogenesis through indirect regulation of Mef2C activity
No full textMicroRNAs represent a group of functional non-coding RNAs (ncRNA) with a role in both translational repression and/or RNAi-mediated degradation of specific target mRNAs. Reports indicate that microRNA regulation plays an important role in numerous cellular processes. We have identified microRNAs regulated during induction of neurogenesis in an in vitro model, and have correlated the expression of these specific microRNAs to regulated mRNAs with the goal of describing potential functional interactions between the two sets of molecules. We demonstrate the active role these regulated microRNAs play in inducing a neuronal phenotype in uncommitted neural precursor cells. As a result of this analysis, as well as additional studies of regulated mRNA transcripts during neurogenesis, we have identified a regulated transcription factor, Mef2C, which is chromosomally adjacent to one of the regulated microRNAs. The unexpected appearance of this transcription factor and its relatively unexplored role in neural differentiation suggest that Mef2C may play a role in this cellular process. This single genomic locus containing an induced microRNA involved in neuronal fate determination, as well as Mef2C, is transcriptionally regulated during neuronal cell specification. In addition, HDAC4, a known repressor of Mef2C activity is validated as a target for miR-9 mediated post-transcriptional repression. Described here is a putative network of interactions that arise from transcriptional activation of this locus, with the end result contributing to the induction of a neuronal phenotype.Ph.D.Includes bibliographical references (p. 96-110)
Long Noncoding RNAs: Central to Nervous System Development
No full textThe development of the central nervous system (CNS) is a complex orchestration of stem cells, transcription factors, growth/differentiation factors, and epigenetic control. Noncoding RNAs have been identified, classified, and studied for their functional roles in many systems including the CNS. In particular, the class of long noncoding RNAs (lncRNAs) has generated both enthusiasm and skepticism due to the unexpected discovery, the diversity of mechanisms, and the lower level of expression than found in protein-coding RNAs. Here we describe evidence supporting the role of lncRNAs in driving CNS-specific differentiation. It is clear that lncRNAs exhibit a functional diversity that makes their study and compartmentalization more challenging than other classes of noncoding RNAs. We predict, however, that lncRNAs will be essential for the characterization of discrete neuronal cell types in the age of single-cell transcriptomics and that these regulatory RNAs contribute to the multitude of functional mechanisms during CNS differentiation that will rival the diversities of protein-based mechanisms.Peer reviewe
Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain
Full text linkLong noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNA-null mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring protein-coding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.National Science Foundation (U.S.) (Postdoctoral Research Fellowship in Biology DBI-0905973
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Spatial transcriptomics of layer 4 of the mouse posteromedial barrel subfield reveals gradients of gene expression and differential transcriptional responses to experience dependent plasticity
No full textPast studies have demonstrated cortical region-specific gene expression patterns. Recent research on cytoarchitectonic variations and gradients of functional specialization within a cortical region, however, suggests the importance of local transcriptional variations within cortical regions. In my thesis work, I took advantage of the topographically organized mouse posteromedial barrel subfield (PMBSF), and spatially resolved transcriptomic profiling, to test the hypothesis that there exist spatial transcriptional gradients across the tangential orientation of layer 4 (L4) in the mouse PMBSF. We identified multiple tangential transcriptional gradients within L4, which were correlated with spatial location. Another focus of my thesis work is transcriptional changes in response to long-term experience dependent plasticity (EDP), which is essential for an animal’s survival in an ever-changing environment. Prior research on activity-dependent gene expression primarily focused on short-term (hours) changes. Yet long-term (days or weeks) transcriptional changes are pertinent to structural and physiological changes of neurons, and learning and adaptation of animals. Moreover, few studies have sought to determine the differential deprived and spared responses in the transcriptomes. Here we used the topographically organized mouse PMBSF L4 and spatial transcriptomics to test the hypothesis that differential transcriptional responses occur in the deprived and spared barrels following seven days of chessboard pattern whisker deprivation. Analysis of differentially used genes and gene co-regulatory networks revealed biological processes enriched in the deprived or the spared barrels, including those related to ribosome and translation, neuropeptide signaling, microglial function, and regulation of synaptic transmission
Uncovering Novel Insights into Retinal Diseases Using Single-Cell Transcriptional Profiling
Full text linkDroplet-based single-cell RNA sequencing (scRNAseq) has emerged as a powerful tool to simultaneously profile the transcriptomes of tens of thousands of cells in the same tissue. In this thesis, I utilized scRNAseq to profile gene expression changes at single-cell resolution in two retinal disease models that recapitulate two common themes in retinal disease - hypoxia and inflamma- tion. The first model, the Norrin knockout (NdpKO) mouse, is a model of fa- milial exudative vitreoretinopathy (FEVR), in which developmental hypovas- cularization of the retina produces chronic hypoxia of inner nuclear layer (INL) neurons and Muller glia. I have used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13C-glucose to compare wild type and NdpKO retinas. In NdpKO retinas, I observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and a metabolic shift that combines reduced flux through the tricarboxylic acid cycle with in- creased synthesis of serine, glycine, and glutathione. I also used single-cell RNA sequencing to compare the responses of individual cell types in NdpKO retinas to those in the hypoxic cerebral cortex of mice that were housed for one week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the re- sponse of Muller glia in the NdpKO retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression pro- gram, which likely underlies the adaptive neo-angiogenic response to chronic hypoxia. The second model is the Aire-/- mouse, which develops autoimmune uveitis through the loss of central tolerance. scRNAseq revealed Th1 cells as the dominant effector T helper cells in this disease model as well as a dynamic Th1 self-regulatory state. Furthermore, scRNAseq was able to capture the dynamic phenotypes adopted by infiltrating monocytes, including a microglial- like phenotype. Finally, scRNAseq was able to simultaneously profile the tran- scriptional response of the resident retinal cells and found a strong interferon gamma-stimulation signature, consistent with a Th1 effector mechanism. In summary, I have used scRNAseq to uncover novel and context-specific insights in retinal disease models. Understanding such disease mechanisms could allow us to design rational strategies to treat or even prevent retinal diseases
Spatial transcriptomics of layer 4 of the mouse posteromedial barrel subfield reveals gradients of gene expression and differential transcriptional responses to experience dependent plasticity
No full textPast studies have demonstrated cortical region-specific gene expression patterns. Recent research on cytoarchitectonic variations and gradients of functional specialization within a cortical region, however, suggests the importance of local transcriptional variations within cortical regions. In my thesis work, I took advantage of the topographically organized mouse posteromedial barrel subfield (PMBSF), and spatially resolved transcriptomic profiling, to test the hypothesis that there exist spatial transcriptional gradients across the tangential orientation of layer 4 (L4) in the mouse PMBSF. We identified multiple tangential transcriptional gradients within L4, which were correlated with spatial location. Another focus of my thesis work is transcriptional changes in response to long-term experience dependent plasticity (EDP), which is essential for an animal’s survival in an ever-changing environment. Prior research on activity-dependent gene expression primarily focused on short-term (hours) changes. Yet long-term (days or weeks) transcriptional changes are pertinent to structural and physiological changes of neurons, and learning and adaptation of animals. Moreover, few studies have sought to determine the differential deprived and spared responses in the transcriptomes. Here we used the topographically organized mouse PMBSF L4 and spatial transcriptomics to test the hypothesis that differential transcriptional responses occur in the deprived and spared barrels following seven days of chessboard pattern whisker deprivation. Analysis of differentially used genes and gene co-regulatory networks revealed biological processes enriched in the deprived or the spared barrels, including those related to ribosome and translation, neuropeptide signaling, microglial function, and regulation of synaptic transmission
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