Dicer Is Required for Maintaining Adult Pancreas

Morita, Sumiyo; Hara, Akemi; Kojima, Itaru; Horii, Takuro; Kimura, Masashi; Kitamura, Tadahiro; Ochiya, Takahiro; Nakanishi, K.; Matoba, Ryo; Matsubara, Kazuo; Hatada, Izuho

doi:10.1371/journal.pone.0004212

Cited by 42 publications

(29 citation statements)

References 34 publications

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“…This is also supported by the fact that postdevelopment ␤ cell-specific deletion of Dicer had no effect on ␤-cell proliferation or maintenance. On the other hand, a generalized Dicer-hypomorphic knockout model with only ϳ20% residual dicer in all tissues, displayed abnormalities in the adult pancreas in the form of irregular distribution of islet cells, an increase in the number of ductal insulinϩ/glucagonϩ/Pdx-1 epithelial cells, and abnormal multinucleated cells, which argued that miRNAs might be regulating progenitor cell proliferation and differentiation in this organ (431).…”

Section: A Mirnas In Pancreas Development and Functionmentioning

confidence: 99%

MicroRNAs in Development and Disease

Sayed¹,

Abdellatif

2011

Physiological Reviews

942

720

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LSayed D, Abdellatif M. MicroRNAs in Development and Disease. Physiol Rev 91: 827-887, 2011; doi:10.1152/physrev.00006.2010 are a class of posttranscriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. There are currently over 10,000 miRNAs that have been identified in a range of species including metazoa, mycetozoa, viridiplantae, and viruses, of which 940, to date, are found in humans. It is estimated that more than 60% of human protein-coding genes harbor miRNA target sites in their 3= untranslated region and, thus, are potentially regulated by these molecules in health and disease. This review will first briefly describe the discovery, structure, and mode of function of miRNAs in mammalian cells, before elaborating on their roles and significance during development and pathogenesis in the various mammalian organs, while attempting to reconcile their functions with our existing knowledge of their targets. Finally, we will summarize some of the advances made in utilizing miRNAs in therapeutics.

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Section: A Mirnas In Pancreas Development and Functionmentioning

confidence: 99%

MicroRNAs in Development and Disease

Sayed¹,

Abdellatif

2011

Physiological Reviews

942

720

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“…Whole-body deletion of Dicer1 in mice results in early embryonic lethality [11] but, surprisingly, Dicer1-hypomorphic mice, expressing about 20% of wild type Dicer1 level, are viable and display histologically normal tissue development throughout fetal and neonatal stages. However, starting from 4 weeks of age, the pancreas showed morphologic abnormalities [12]. Lynn and colleagues generated a pancreatic Dicer1-null mice who survived until birth but died at 3 days of age (P3) [13].…”

Section: Evidence For the Involvement Of Mirnas In The Control Of Panmentioning

confidence: 99%

MicroRNAs and the functional β cell mass: For better or worse

Guay

Regazzi

2015

Diabetes & Metabolism

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Insulin secretion from pancreatic β-cells plays a central role in the control of blood glucose levels. The amount of insulin released by β-cells is precisely adjusted to match the organism requirements. A number of conditions occurring during life, including pregnancy and obesity, can result in a decrease in the sensitivity of insulin target tissues and in the consequent rise in the insulin needs. To preserve glucose homeostasis, the augmented insulin demand requires a compensatory expansion of the mass of pancreatic β-cells and an increase in their secretory activity. This compensatory process is known to be accompanied by modifications in β-cell gene expression but the molecular mechanisms underlying this phenomenon are still poorly understood. Emerging evidence indicate that at least part of these compensatory events may be orchestrated by changes in the level of a novel class of gene regulators, the microRNAs.Indeed, several of these small non-coding RNAs have either positive or negative impacts on β-cell proliferation and survival. The studies reviewed in this paper suggest that the balance between the actions of these two groups of microRNAs with opposing functional effects determines whether β-cells expand sufficiently to maintain blood glucose levels in the normal range or fail to meet the insulin demand with a consequent progression toward diabetes manifestation. A better understanding of the mechanisms governing the changes in the microRNA profile will open the way for the development of new strategies to prevent and/or treat type 2 and gestational diabetes.

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“…Deletion of Dicer1 at different stages of pancreas development or of the pancreatic endocrine lineage results in a dramatic loss of microRNAs, accompanied by severe defects in pancreas morphology, islet organisation, beta cell formation and insulin biosynthesis [6][7][8]. The precise role of microRNAs in insulinsecreting cells has been investigated by deleting Dicer1 specifically in beta cells.…”

Section: Micrornas As Regulators Of Beta Cell Differentiation and Funmentioning

confidence: 99%

Role of islet microRNAs in diabetes: which model for which question?

Guay

Regazzi

2014

Diabetologia

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MicroRNAs are important regulators of gene expression. The vast majority of the cells in our body rely on hundreds of these tiny non-coding RNA molecules to precisely adjust their protein repertoire and faithfully accomplish their tasks. Indeed, alterations in the microRNA profile can lead to cellular dysfunction that favours the appearance of several diseases. A specific set of microRNAs plays a crucial role in pancreatic beta cell differentiation and is essential for the fine-tuning of insulin secretion and for compensatory beta cell mass expansion in response to insulin resistance. Recently, several independent studies reported alterations in microRNA levels in the islets of animal models of diabetes and in islets isolated from diabetic patients. Surprisingly, many of the changes in microRNA expression observed in animal models of diabetes were not detected in the islets of diabetic patients and vice versa. These findings are unlikely to merely reflect species differences because microRNAs are highly conserved in mammals. These puzzling results are most probably explained by fundamental differences in the experimental approaches which selectively highlight the microRNAs directly contributing to diabetes development, the microRNAs predisposing individuals to the disease or the microRNAs displaying expression changes subsequent to the development of diabetes. In this review we will highlight the suitability of the different models for addressing each of these questions and propose future strategies that should allow us to obtain a better understanding of the contribution of microRNAs to the development of diabetes mellitus in humans.Keywords Animal models of Diabetes . Diabetes . Human islet donors . Insulin . Islets of Langerhans . MicroRNAs . Pancreatic beta cells . Review MicroRNAs as regulators of beta cell differentiation and functionType 2 diabetes is a chronic metabolic disorder characterised by major alterations in gene expression, which affects several organs, including the islets of Langerhans. A growing number of studies demonstrate that these changes are not only caused by deregulation of key transcription factors such as v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MafA) or pancreatic and duodenal homeobox 1 (PDX1) but are also driven by modifications in the level of another group of molecules regulating gene expression, the microRNAs [1][2][3][4]. MicroRNAs are small non-coding RNAs (typically 21-23 nucleotides long) that pair to the 3′ untranslated region of target mRNAs leading to translational repression and/or a decrease in messenger stability [5].The importance of the microRNA regulatory network for proper differentiation and function of beta cells is highlighted by the phenotypic traits of mice lacking Dicer1, an enzyme essential for the generation of most microRNAs [5]. Deletion of Dicer1 at different stages of pancreas development or of the pancreatic endocrine lineage results in a dramatic loss of microRNAs, accompanied by severe defects in pancreas m...

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Dicer Is Required for Maintaining Adult Pancreas

Cited by 42 publications

References 34 publications

MicroRNAs in Development and Disease

MicroRNAs in Development and Disease

MicroRNAs and the functional β cell mass: For better or worse

Role of islet microRNAs in diabetes: which model for which question?

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