scholarly journals The Challenges and Opportunities in the Development of MicroRNA Therapeutics: A Multidisciplinary Viewpoint

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3097
Author(s):  
Mohammad Yahya Momin ◽  
Ravinder Reddy Gaddam ◽  
Madeline Kravitz ◽  
Anisha Gupta ◽  
Ajit Vikram
Keyword(s):  
Target Identification ◽  
Critical Role ◽  
Adverse Outcomes ◽  
Phase Iii ◽  
Cell Type ◽  
Challenges And Opportunities ◽  
Sequence Complementarity ◽  
Cell Type Specific ◽  
Functional Complexity ◽  
Independent Effects

microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR’s role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR’s role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics.

scholarly journals Roles of GPRC5 family proteins: focusing on GPRC5B and lipid-mediated signalling

2020 ◽  
Vol 167 (6) ◽  
pp. 541-547 ◽  
Author(s):  
Yoshio Hirabayashi ◽  
Yeon-Jeong Kim
Keyword(s):  
Cancer Progression ◽  
Knockout Mouse ◽  
Critical Role ◽  
The Body ◽  
Sphingolipid Metabolism ◽  
Gene Products ◽  
Cell Type ◽  
The Past ◽  
Cell Type Specific ◽  
And Control

Abstract In the past decade, physiological roles and molecular functions of GPRC5 family receptors, originally identified as retinoic acid-induced gene products, have been uncovered, even though their intrinsic agonists are still a mystery. They are differentially distributed in certain tissues and cells in the body suggesting that cell-type-specific regulations and functions are significant. Molecular biological approaches and knockout mouse studies reveal that GPRC5 family proteins have pivotal roles in cancer progression and control of metabolic homeostasis pathways. Remarkably, GPRC5B-mediated tyrosine-phosphorylation signalling cascades play a critical role in development of obesity and insulin resistance through dynamic sphingolipid metabolism.

scholarly journals Spatially patterned excitatory neuron subtypes and circuits within the claustrum

2021 ◽  
Author(s):  
Sarah R Erwin ◽  
Brianna N Bristow ◽  
Kaitlin E Sullivan ◽  
Brian Marriott ◽  
Lihua Wang ◽  
...  
Keyword(s):  
Neural Circuits ◽  
Spatial Arrangement ◽  
Retrograde Tracing ◽  
Excitatory Neuron ◽  
Cell Type ◽  
Narrow Region ◽  
Single Cell Rna Sequencing ◽  
Cell Type Specific ◽  
Functional Complexity

The claustrum is a functionally and structurally complex brain region, whose very spatial extent remains debated. Histochemical-based approaches typically treat the claustrum as a relatively narrow region that primarily projects to the neocortex, whereas circuit-based approaches suggest a broader region embedding neocortical and other neural circuits. Here, we took a bottom up, cell-type-specific approach to complement and possibly unite these seemingly disparate conclusions. Using single-cell RNA-sequencing, we found that the claustrum is comprised of two excitatory neuron subtypes that are differentiable from the surrounding cortex. Multicolor retrograde tracing in conjunction with 12-channel multiplexed in situ hybridization revealed a core-shell spatial arrangement of these subtypes, as well as differential projection targets. Thus, the claustrum is comprised of excitatory neuron subtypes with distinct molecular and circuit properties, whose spatial patterns reflect the narrower and broader claustral extents debated in previous research. This subtype-specific heterogeneity likely shapes the functional complexity of the claustrum.

Notch/HES1 Signaling Stabilizes p53 Expression Via a Novel PARP1-Chfr-PLK1-Mediated Mechanism in B-ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1292-1292
Author(s):  
Sankaranarayanan Kannan ◽  
Patrick A Zweidler-McKay
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
B Cell ◽  
Notch Signaling ◽  
Critical Role ◽  
Growth Arrest ◽  
Cyclin B ◽  
Cell Type ◽  
Cell Type Specific ◽  
Notch Activation

Abstract Abstract 1292 Background: Notch signaling contributes to T cell leukemogenesis. However, we have found that activation of Notch signaling in human B-ALL promotes growth arrest and apoptosis. These contrasting effects of Notch in B versus T cell ALL, mirror effects seen in early lymphocyte development. As the Notch receptors are common between T and B cells, we hypothesized that these differences rely on the cell-type specific downstream mechanisms. We previously reported a critical role for Notch/HES1-mediated activation of Poly ADP-Ribose Polymerase 1 (PARP1) function in this B cell specific mechanism. Approach: To explore the cell-type specific downstream mechanisms of Notch activation in B-ALL, we used cell fractionation, westerns and immunoprecipitation to identify cell cycle regulators which were altered by Notch activation via HES1 expression in human B-ALL lines. Results: Notch activation in a panel of human B-ALL lines led to consistent growth arrest and apoptosis. Indeed, ligands, activated receptors and the Notch target gene HES1 all induced these leukemia lihibiting effects in B-ALL but not T-ALL lines. In this study we report a mechanism whereby HES1-mediated activation of PARP1 leads to PARylation of the E3 ligase Checkpoint with FHA and RING finger (CHFR) (Panel A) which results in targeting and ubiquitination of the cell cycle regulator Polo-Like Kinase 1 (PLK1) (Panel B). PLK1 is highly expressed in B vs. T-ALL and plays a critical role in B cell growth and survival. Following Notch activation, loss of ubiquitionated PLK1 through proteosomal degradation leads to cell cycle arrest through two mechanisms, namely cytoplasmic relocalization of cyclin B, disrupting the CDC2-cyclinB complex, as well as phosphorylation of p53 at S20, which leads to decreased weakened p53-MDM2 interaction and accumulation of p53 (Panel C). siRNA to CHFR reveal that this mechanism is dependent on CHFR (Panel C). Importantly this mechanism is not seen in T-ALL cells as the activation of PARP1 by HES1 does not occur in T-ALL cells. Conclusions: Our findings reveal a novel molecular mechanism whereby Notch signaling induces disruption of the cell cycle in a cell type specific manner in B-ALL. Activation of PARP1, PARylation of CHFR, ubiquitination of PLK1 resulting in loss of nuclear cyclin B and accumulation of p53 demonstrates a series of events which can be initiated through activation of Notch in B-ALL. This mechanism reveals a potentially targetable approach to B-ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation

BMC Cancer ◽  
2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Kamil Gotfryd ◽  
Galina Skladchikova ◽  
Eugene A Lepekhin ◽  
Vladimir Berezin ◽  
Elisabeth Bock ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Type ◽  
Hdac Activity ◽  
Anti Cancer ◽  
Cell Type Specific ◽  
Independent Effects

scholarly journals Laminar Organization of the Entorhinal Cortex in Macaque Monkeys Based on Cell-Type-Specific Markers and Connectivity

2021 ◽  
Vol 15 ◽  
Author(s):  
Shinya Ohara ◽  
Rintaro Yoshino ◽  
Kei Kimura ◽  
Taichi Kawamura ◽  
Soshi Tanabe ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Entorhinal Cortex ◽  
Critical Role ◽  
Cell Protein ◽  
Cell Type ◽  
Laminar Organization ◽  
Macaque Monkeys ◽  
Genetic Tools ◽  
Cell Type Specific ◽  
Layer V

The entorhinal cortex (EC) is a major gateway between the hippocampus and telencephalic structures, and plays a critical role in memory and navigation. Through the use of various molecular markers and genetic tools, neuron types constituting EC are well studied in rodents, and their layer-dependent distributions, connections, and functions have also been characterized. In primates, however, such cell-type-specific understandings are lagging. To bridge the gap between rodents and primates, here we provide the first cell-type-based global map of EC in macaque monkeys. The laminar organization of the monkey EC was systematically examined and compared with that of the rodent EC by using immunohistochemistry for molecular markers which have been well characterized in the rodent EC: reelin, calbindin, and Purkinje cell protein 4 (PCP4). We further employed retrograde neuron labeling from the nucleus accumbens and amygdala to identify the EC output layer. This cell-type-based approach enabled us to apply the latest laminar definition of rodent EC to monkeys. Based on the similarity of the laminar organization, the monkey EC can be divided into two subdivisions: rostral and caudal EC. These subdivisions likely correspond to the lateral and medial EC in rodents, respectively. In addition, we found an overall absence of a clear laminar arrangement of layer V neurons in the rostral EC, unlike rodents. The cell-type-based architectural map provided in this study will accelerate the application of genetic tools in monkeys for better understanding of the role of EC in memory and navigation.

Regulation of the PU.1 gene by distal elements

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 2958-2965 ◽  
Author(s):  
Youlin Li ◽  
Yutaka Okuno ◽  
Pu Zhang ◽  
Hanna S. Radomska ◽  
Hui-min Chen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Transcriptional Start Site ◽  
Critical Role ◽  
Myeloid Cell ◽  
Regulatory Elements ◽  
Cell Type ◽  
Specific Expression ◽  
Deoxyribonuclease I ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

Abstract The transcription factor PU.1 (also known as Spi-1) plays a critical role in the development of the myeloid lineages, and myeloid cells derived from PU.1−/− animals are blocked at the earliest stage of myeloid differentiation. Expression of the PU.1 gene is tightly regulated during normal hematopoietic development, and dysregulation of PU.1 expression can lead to erythroleukemia. However, relatively little is known about how the PU.1 gene is regulated in vivo. Here it is shown that myeloid cell type–specific expression of PU.1 in stable cell lines and transgenic animals is conferred by a 91-kilobase (kb) murine genomic DNA fragment that consists of the entire PU.1 gene (20 kb) plus approximately 35 kb of upstream and downstream sequences, respectively. To further map the important transcriptional regulatory elements, deoxyribonuclease I hypersensitive site mapping studies revealed at least 3 clusters in the PU.1 gene. A 3.5-kb fragment containing one of these deoxyribonuclease I hypersensitive sites, located −14 kb 5′ of the transcriptional start site, conferred myeloid cell type–specific expression in stably transfected cell lines, suggesting that within this region is an element important for myeloid specific expression of PU.1. Further analysis of this myeloid-specific regulatory element will provide insight into the regulation of this key transcriptional regulator and may be useful as a tool for targeting expression to the myeloid lineage.

scholarly journals Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Steven A Hill ◽  
Andrew S Blaeser ◽  
Austin A Coley ◽  
Yajun Xie ◽  
Katherine A Shepard ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Neuronal Excitability ◽  
Synapse Formation ◽  
Critical Role ◽  
K Channel ◽  
Synaptic Organization ◽  
Cell Type ◽  
Shh Signaling ◽  
Cell Type Specific

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling in mature astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.

scholarly journals Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization

2019 ◽  
Author(s):  
Steven Hill ◽  
Andrew Blaeser ◽  
Austin A. Coley ◽  
Yajun Xie ◽  
Katherine A. Shepard ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Neuronal Excitability ◽  
Synapse Formation ◽  
Critical Role ◽  
Synaptic Organization ◽  
Cell Type ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Cell Type Specific

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling between neurons and astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.

scholarly journals Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

2021 ◽  
Vol 9 ◽  
Author(s):  
Puja Agrawal ◽  
Sridhar Rao
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Critical Role ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Cell Type ◽  
Mammalian Development ◽  
Cell Fate Decisions ◽  
Cell Type Specific ◽  
Early Mammalian Development

Cell fate decisions are the backbone of many developmental and disease processes. In early mammalian development, precise gene expression changes underly the rapid division of a single cell that leads to the embryo and are critically dependent on autonomous cell changes in gene expression. To understand how these lineage specifications events are mediated, scientists have had to look past protein coding genes to the cis regulatory elements (CREs), including enhancers and insulators, that modulate gene expression. One class of enhancers, termed super-enhancers, is highly active and cell-type specific, implying their critical role in modulating cell-type specific gene expression. Deletion or mutations within these CREs adversely affect gene expression and development and can cause disease. In this mini-review we discuss recent studies describing the potential roles of two CREs, enhancers and binding sites for CTCF, in early mammalian development.

scholarly journals Gelsolin and dCryAB act downstream of muscle identity genes and contribute to preventing muscle splitting and branching in Drosophila

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Benjamin Bertin ◽  
Yoan Renaud ◽  
Teresa Jagla ◽  
Guillaume Lavergne ◽  
Cristiana Dondi ◽  
...  
Keyword(s):  
Body Wall ◽  
Critical Role ◽  
Interacting Proteins ◽  
Cell Type ◽  
Larval Body ◽  
A Cell ◽  
Body Wall Muscles ◽  
Cell Type Specific ◽  
Muscle Types ◽  
Identify Gene Expression

AbstractA combinatorial code of identity transcription factors (iTFs) specifies the diversity of muscle types in Drosophila. We previously showed that two iTFs, Lms and Ap, play critical role in the identity of a subset of larval body wall muscles, the lateral transverse (LT) muscles. Intriguingly, a small portion of ap and lms mutants displays an increased number of LT muscles, a phenotype that recalls pathological split muscle fibers in human. However, genes acting downstream of Ap and Lms to prevent these aberrant muscle feature are not known. Here, we applied a cell type specific translational profiling (TRAP) to identify gene expression signatures underlying identity of muscle subsets including the LT muscles. We found that Gelsolin (Gel) and dCryAB, both encoding actin-interacting proteins, displayed LT muscle prevailing expression positively regulated by, the LT iTFs. Loss of dCryAB function resulted in LTs with irregular shape and occasional branched ends also observed in ap and lms mutant contexts. In contrast, enlarged and then split LTs with a greater number of myonuclei formed in Gel mutants while Gel gain of function resulted in unfused myoblasts, collectively indicating that Gel regulates LTs size and prevents splitting by limiting myoblast fusion. Thus, dCryAB and Gel act downstream of Lms and Ap and contribute to preventing LT muscle branching and splitting. Our findings offer first clues to still unknown mechanisms of pathological muscle splitting commonly detected in human dystrophic muscles and causing muscle weakness.

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