Pancreas-enriched miRNA refines endocrine cell differentiation

Kredo‐Russo, Sharon; Mandelbaum, Amitai D.; Ness, A. T.; Alon, Ilana; Lennox, Kim A.; Behlke, Mark A.; Hornstein, Eran

doi:10.1242/dev.080127

Cited by 101 publications

(90 citation statements)

References 51 publications

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“…These findings add to the accumulating evidence of multiple miRNAs involved in pancreatic b-cell development, regeneration, and function (4,5).…”

supporting

confidence: 60%

“…It is rapidly becoming apparent that they play an important regulatory role in disease states, mostly commonly studied in development, cancer, and cardiovascular disease, to name a few examples (3). More recently, their role in diabetes has been studied both in relation to the changes in metabolic tissues, control of pancreatic islet mass and b-cell function, such as insulin secretion, and their roles in diabetes complications (4,5).…”

mentioning

confidence: 99%

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microRNAs: What the Clinician Should Know About This New Frontier

LeRoith

2014

Diabetes Care

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“…These findings add to the accumulating evidence of multiple miRNAs involved in pancreatic b-cell development, regeneration, and function (4,5).…”

supporting

confidence: 60%

mentioning

confidence: 99%

microRNAs: What the Clinician Should Know About This New Frontier

LeRoith

2014

Diabetes Care

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“…The prominent roles for Pax genes are linked to the perturbed expression of Pax genes seen in disease states. Importantly, miR-mediated regulation of Pax proteins (Pasut and Rudnicki, 2012;Kredo-Russo et al, 2012;Shalom-Feuerstein et al, 2012;Shaham et al, 2013) and the role of Pax proteins in the epigenetic determination of active or silenced regions of DNA is now coming to light that adds further complexity to the causes and repercussions of aberrant Pax gene expression that fuels oncogenesis and other disease.…”

Section: Discussionmentioning

confidence: 99%

Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. KEY WORDS: Pax genes, Embryogenesis, Lineage determination IntroductionPaired box (Pax) genes encode transcription factors that contain a highly conserved DNA-binding domain called the paired domain (PD, Fig. 1A) and can be considered to be a principle regulator of gene expression. Nine Pax genes (Pax1-Pax9) have been characterised in mammals and the evolutionary conserved paired domain has been identified across phylogenies from insects, to amphibians and birds. In higher vertebrates, PAX proteins are subclassified into groups according to inclusion of an additional DNA-binding homeodomain and/or an octapeptide region, which serves as a binding motif for protein co-factors for potent inhibition of downstream gene transcription (Eberhard et al., 2000) (Fig. 1B); all PAX proteins include a transactivation domain located within the C-terminal amino acids (Underhill, 2012). It is also known that all Pax genes, with the exception of Pax4 and Pax9, produce alternative RNA transcripts (see Table 1). The functional diversity of Pax proteins in vivo is thus linked to the ability to produce alternatively spliced gene products that differ in structure and, consequently, in the binding activity of their paired and homeodomain DNA-binding regions (Underhill, 2012).Three decades ago, the characterisation and roles of Pax genes in embryonic development began to unfold. Early studies discovered that regulatory gene families such as the Pax family are involved in the sequential compartmentalisation and body patterning of developing organisms; thereafter, studies highlighted a role for Pax genes in the early specification of cell fate and the subsequent morphogenesis of various tissues and organs. Following this, mutational studies of Pax genes confirmed the importance of these regulatory roles in the PRIMER School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.*Author for correspondence (j.blake@ecu.edu.au) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.initiation and progression of ...

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“…Of all miR-7-regulated transcription factors, we confirmed regulation of Pax6 by miR-7a (31) and identified Gata6 as a novel pancreatic transcription factor directly regulated by miR-7. Both PAX6 and GATA6 have been shown to play key roles in pancreatic endocrine differentiation (31,(47)(48)(49)(50). Whereas conditional loss of PAX6 function in the adult pancreas leads to profound hyperglycemia and dedifferentiation of β cells, with a marked reduction in PDX1, NKX6-1, and late markers such as GLUT2 and insulin (51), much less known about the molecular function of GATA6 in adult islet β cells, which retain significant expression levels of the transcription factor (52).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-7a regulates pancreatic β cell function

Latreille¹,

Hausser²,

Stützer³

et al. 2014

J. Clin. Invest.

271

299

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Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates β cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in β cells developed diabetes due to impaired insulin secretion and β cell dedifferentiation. Interestingly, perturbation of miR-7a expression in β cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine β cell mass. Furthermore, we found that miR-7a levels are decreased in obese/ diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated β cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic β cells and support a role for miR-7 in the adaptation of pancreatic β cell function in obesity and type 2 diabetes.

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Pancreas-enriched miRNA refines endocrine cell differentiation

Cited by 101 publications

References 51 publications

microRNAs: What the Clinician Should Know About This New Frontier

microRNAs: What the Clinician Should Know About This New Frontier

Pax genes: regulators of lineage specification and progenitor cell maintenance

MicroRNA-7a regulates pancreatic β cell function

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