scholarly journals Non-Coding RNA in Pancreas and β-Cell Development

2018 ◽  
Vol 4 (4) ◽  
pp. 41 ◽  
Author(s):  
Wilson K. M. Wong ◽  
Anja E. Sørensen ◽  
Mugdha V. Joglekar ◽  
Anand A. Hardikar ◽  
Louise T. Dalgaard
Keyword(s):  
Cell Function ◽  
Islet Cells ◽  
Current Knowledge ◽  
Cell Development ◽  
Pancreas Development ◽  
Β Cell ◽  
Neighboring Gene ◽  
Non Coding Rnas ◽  
And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

scholarly journals POLIII-derived non-coding RNAs acting as scaffolds and decoys

2019 ◽  
Vol 11 (10) ◽  
pp. 880-885 ◽  
Author(s):  
Hendrik Täuber ◽  
Stefan Hüttelmaier ◽  
Marcel Köhn
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Cellular Functions ◽  
Control Of Gene Expression ◽  
Ribonucleoprotein Complexes ◽  
Small Ncrnas ◽  
Non Coding Rnas ◽  
And Function

Abstract A large variety of eukaryotic small structured POLIII-derived non-coding RNAs (ncRNAs) have been described in the past. However, for only few, e.g. 7SL and H1/MRP families, cellular functions are well understood. For the vast majority of these transcripts, cellular functions remain unknown. Recent findings on the role of Y RNAs and other POLIII-derived ncRNAs suggest an evolutionarily conserved function of these ncRNAs in the assembly and function of ribonucleoprotein complexes (RNPs). These RNPs provide cellular `machineries’, which are essential for guiding the fate and function of a variety of RNAs. In this review, we summarize current knowledge on the role of POLIII-derived ncRNAs in the assembly and function of RNPs. We propose that these ncRNAs serve as scaffolding factors that `chaperone’ RNA-binding proteins (RBPs) to form functional RNPs. In addition or associated with this role, some small ncRNAs act as molecular decoys impairing the RBP-guided control of RNA fate by competing with other RNA substrates. This suggests that POLIII-derived ncRNAs serve essential and conserved roles in the assembly of larger RNPs and thus the control of gene expression by indirectly guiding the fate of mRNAs and lncRNAs.

scholarly journals Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic β-Cell Function

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2072-2079 ◽  
Author(s):  
Eva Hammar ◽  
Alejandra Tomas ◽  
Domenico Bosco ◽  
Philippe A. Halban
Keyword(s):  
Extracellular Matrix ◽  
Insulin Secretion ◽  
Actin Cytoskeleton ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
And Function

Extracellular matrix has a beneficial impact on β-cell spreading and function, but the underlying signaling pathways have yet to be fully elucidated. In other cell types, Rho, a well-characterized member of the family of Rho GTPases, and its effector Rho-associated kinase (ROCK), play an important role as downstream mediators of outside in signaling from extracellular matrix. Therefore, a possible role of the Rho-ROCK pathway in β-cell spreading, actin cytoskeleton dynamics, and function was investigated. Rho was inhibited using a new cell-permeable version of C3 transferase, whereas the activity of ROCK was repressed using the specific ROCK inhibitors H-1152 and Y-27632. Inhibition of Rho and of ROCK increased spreading and improved both short-term and prolonged glucose-stimulated insulin secretion but had no impact on basal secretion. Inhibition of this pathway led to a depolymerization of the actin cytoskeleton. Furthermore, the impact of the inhibition of ROCK on stimulated insulin secretion was acute and reversible, suggesting that rapid signaling such as phosphorylation is involved. Finally, quantification of the activity of RhoA indicated that the extracellular matrix represses RhoA activity. Overall these results show for the first time that the Rho-ROCK signaling pathway contributes to the stabilization of the actin cytoskeleton and inhibits glucose-stimulated insulin secretion in primary pancreatic β-cells. Furthermore, they indicate that inhibition of this pathway might be one of the mechanisms by which the extracellular matrix exerts its beneficial effects on pancreatic β-cell function.

scholarly journals Integrin α3, But Not β1, Regulates Islet Cell Survival and Function via PI3K/Akt Signaling Pathways

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 424-435 ◽  
Author(s):  
Mansa Krishnamurthy ◽  
Jinming Li ◽  
George F. Fellows ◽  
Lawrence Rosenberg ◽  
Cynthia G. Goodyer ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Function ◽  
Islet Cells ◽  
Glycogen Synthase ◽  
Specific Effect ◽  
Signaling Cascades ◽  
Β1 Integrin ◽  
Β Cell ◽  
Downstream Signaling ◽  
And Function

Abstract β1-Integrin is a well-established regulator of β-cell activities; however, the role of its associated α-subunits is relatively unknown. Previously, we have shown that human fetal islet and INS-1 cells highly express α3β1-integrin and that collagens I and IV significantly enhance their survival and function; in addition, blocking β1 function in the fetal islet cells decreased adhesion on collagen I and increased apoptosis. The present study investigates the effect of blocking α3. Using α3 blocking antibody or small interfering RNA, the effects of α3-integrin blockade were examined in isolated human fetal or adult islet cells or INS-1 cells, cultured on collagens I or IV. In parallel, β1 blockade was analyzed in INS-1 cells. Perturbing α3 function in human islet or INS-1 cells resulted in significant decreases in cell function (adhesion, spreading, proliferation and Pdx1 and insulin expression/secretion), primarily on collagen IV. A significant decrease in focal adhesion kinase and ERK1/2 phosphorylation and increased caspase3 cleavage were observed on both collagens. These effects were similar to changes after β1 blockade. Interestingly, only α3 blockade reduced expression of phospho-Akt and members of its downstream signaling cascades (glycogen synthase kinase β and X-linked inhibitor of apoptosis), demonstrating a specific effect of α3 on the phosphatidylinositol 3-kinase/Akt pathway. These results suggest that α3- as well as β1-integrin-extracellular matrix interactions are critical for modulating β-cell survival and function through specialized signaling cascades and enhance our understanding of how to improve islet microenvironments for cell-based treatments of diabetes.

scholarly journals Groucho co-repressor proteins regulate β cell development and proliferation by repressing Foxa1 in the developing mouse pancreas

Development ◽  
2021 ◽  
Vol 148 (6) ◽  
Author(s):  
Alexandra Theis ◽  
Ruth A. Singer ◽  
Diana Garofalo ◽  
Alexander Paul ◽  
Anila Narayana ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Ectopic Expression ◽  
Cell Development ◽  
Mouse Genetics ◽  
Pancreas Development ◽  
Β Cell ◽  
Repressor Proteins ◽  
Early Lethality

ABSTRACT Groucho-related genes (GRGs) are transcriptional co-repressors that are crucial for many developmental processes. Several essential pancreatic transcription factors are capable of interacting with GRGs; however, the in vivo role of GRG-mediated transcriptional repression in pancreas development is still not well understood. In this study, we used complex mouse genetics and transcriptomic analyses to determine that GRG3 is essential for β cell development, and in the absence of Grg3 there is compensatory upregulation of Grg4. Grg3/4 double mutant mice have severe dysregulation of the pancreas gene program with ectopic expression of canonical liver genes and Foxa1, a master regulator of the liver program. Neurod1, an essential β cell transcription factor and predicted target of Foxa1, becomes downregulated in Grg3/4 mutants, resulting in reduced β cell proliferation, hyperglycemia, and early lethality. These findings uncover novel functions of GRG-mediated repression during pancreas development.

scholarly journals Cellular autophagy in α cells plays a role in the maintenance of islet architecture

2019 ◽  
Author(s):  
Miwa Himuro ◽  
Takeshi Miyatsuka ◽  
Luka Suzuki ◽  
Masaki Miura ◽  
Takehiro Katahira ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Cell Function ◽  
Multilayered Structure ◽  
Β Cell ◽  
Cellular Autophagy ◽  
Β Cell Function ◽  
And Function ◽  
And Control ◽  
Deficient Mice

Abstract Autophagy is known to play a pivotal role in intracellular quality control through the degradation of subcellular damaged organelles and components. Whereas autophagy is essential for maintaining β-cell function in pancreatic islets, it remains unclear as to how the cellular autophagy affects the homeostasis and function of glucagon-secreting α cells. To investigate the role of autophagy in α cells, we generated a mutant mouse model lacking Atg7, a key molecule for autophagosome formation, specifically in α cells. Histological analysis demonstrated an increased number of glucagon-positive cells, with a multilayered structure, in the islets under Atg7 deficiency, although metabolic profiles, such as body weight, blood glucose and plasma glucagon levels, were comparable between Atg7-deficient mice and control littermates. Consistent with our previous findings that Atg7 deficiency suppressed β-cell proliferation, cellular proliferation was suppressed in Atg7-deficient α cells. These findings suggest that α-cell autophagy plays a role in maintaining α-cell area and normal islet architecture, but appears to be dispensable for metabolic homeostasis.

The role of class I phosphoinositide 3-kinase in T-cell function and autoimmunity

2007 ◽  
Vol 35 (2) ◽  
pp. 177-180 ◽  
Author(s):  
D.A. Fruman
Keyword(s):  
T Cell ◽  
Drug Targets ◽  
Cell Function ◽  
Current Knowledge ◽  
Class I ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase ◽  
And Function ◽  
Precise Role

PI3K (phosphoinositide 3-kinase) regulates diverse cellular responses in the immune system, and members of this enzyme family are considered attractive drug targets for modulating allergy, inflammation and leukaemia. Clearly it is important to understand the function of PI3K in T-lymphocytes, cells that regulate nearly every aspect of immunity. However, the precise role of PI3K in T-cell development and function has been difficult to determine. In this review, I summarize current knowledge of PI3K function in T-cells, focusing on the class I subgroup of PI3K catalytic and regulatory isoforms. I discuss gene disruption studies in mice that reveal redundant or limited roles for individual isoforms, along with evidence for potential autoimmunity when class IA PI3K signalling is reduced.

scholarly journals Mechanism of Prostacyclin-Induced Potentiation of Glucose-Induced Insulin Secretion

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2612-2622 ◽  
Author(s):  
Ewa Gurgul-Convey ◽  
Katarzyna Hanzelka ◽  
Sigurd Lenzen
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Islet Cells ◽  
Receptor Activation ◽  
Insulin Biosynthesis ◽  
Β Cell ◽  
Atp Production ◽  
Mediators Of Inflammation ◽  
Β Cell Function

Arachidonic acid metabolites are crucial mediators of inflammation in diabetes. Although eicosanoids are established modulators of pancreatic β-cell function, the role of prostacyclin (prostaglandin I2) is unknown. Therefore, this study aimed to analyze the role of prostacyclin in β-cell function. Prostacyclin synthase (PGIS) was weakly expressed in rat islet cells but nevertheless significantly increased by incubation with 30 mM glucose, especially in non-β-cells. PGIS was overexpressed in INS1E cells, and the regulation of insulin secretion was analyzed. PGIS overexpression strongly potentiated glucose-induced insulin secretion along with increased insulin content and ATP production. Importantly, overexpression of PGIS potentiated only nutrient-induced insulin secretion. The effect of PGIS overexpression was mediated by prostacyclin released from insulin-secreting cells and dependent on prostacyclin receptor (IP receptor) activation, with concomitant cAMP production. The cAMP-mediated potentiation of glucose-induced insulin secretion by prostacyclin was independent of the protein kinase A pathway but strongly attenuated by the knockdown of the exchange protein directly activated by cAMP 2 (Epac2), pointing to a crucial role for Epac2 in this process. Thus, prostacyclin is a powerful potentiator of glucose-induced insulin secretion. It improves the secretory capacity by inducing insulin biosynthesis and probably by stimulating exocytosis. Our findings open a new therapeutical perspective for an improved treatment of type 2 diabetes.

The PI3K p110δ controls T-cell development, differentiation and regulation

2007 ◽  
Vol 35 (2) ◽  
pp. 167-171 ◽  
Author(s):  
D.T. Patton ◽  
F. Garçon ◽  
K. Okkenhaug
Keyword(s):  
T Cell ◽  
Cell Function ◽  
T Cell Development ◽  
Cell Development ◽  
Helper T Cells ◽  
Cellular Functions ◽  
Cellular And Humoral Immunity ◽  
And Migration ◽  
And Function

PI3Ks (phosphoinositide 3-kinases) regulate diverse cellular functions such as metabolism, growth, gene expression and migration. The p110δ isoform of PI3K is mainly expressed in cells of the immune system and contributes to cellular and humoral immunity. In the thymus, p110δ and p110γ play complementary roles in regulating the transition through key developmental checkpoints. In addition, p110δ regulates the differentiation of peripheral Th (helper T-cells) towards the Th1 and Th2 lineages. Moreover, p110δ is critical for Treg (regulatory T-cell) function. Here, we review the role of PI3Ks in T-cell development and function.

The Oxford Handbook of the Auditory Brainstem

2018 ◽  
Keyword(s):  
Current Knowledge ◽  
Auditory Pathway ◽  
Auditory Brainstem ◽  
Auditory Midbrain ◽  
Current State ◽  
Neuronal Mechanisms ◽  
Maladaptive Plasticity ◽  
And Function ◽  
Auditory Field

The Oxford Handbook of the Auditory Brainstem provides an in-depth reference to the organization and function of ascending and descending auditory pathways in the mammalian brainstem. Individual chapters are organized along the auditory pathway, beginning with the cochlea and ending with the auditory midbrain. Each chapter provides an introduction to the respective area and summarizes our current knowledge before discussing the disputes and challenges that the field currently faces.The handbook emphasizes the numerous forms of plasticity that are increasingly observed in many areas of the auditory brainstem. Several chapters focus on neuronal modulation of function and plasticity on the synaptic, neuronal, and circuit level, especially during development, aging, and following peripheral hearing loss. In addition, the book addresses the role of trauma-induced maladaptive plasticity with respect to its contribution in generating central hearing dysfunction, such as hyperacusis and tinnitus.The book is intended for students and postdoctoral fellows starting in the auditory field and for researchers of related fields who wish to get an authoritative and up-to-date summary of the current state of auditory brainstem research. For clinical practitioners in audiology, otolaryngology, and neurology, the book is a valuable resource of information about the neuronal mechanisms that are currently discussed as major candidates for the generation of central hearing dysfunction.

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