Foxa2 Controls Vesicle Docking and Insulin Secretion in Mature β Cells

Gao, Nan; White, Peter; Doliba, Nicolai M.; Golson, Maria L.; Matschinsky, Franz M.; Kaestner, Klaus H.

doi:10.1016/j.cmet.2007.08.015

Cited by 80 publications

(78 citation statements)

References 47 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A late-stage deletion in mature b-cells of Foxa2 or both Foxa1/Foxa2 resulted in increased insulin-granule docking and exocytosis, which is the main cause of persistent hyperinsulinemic hypoglycemia. Thus, these Foxa proteins control multiple aspects of insulin secretion in mature b-cells, and regulate many genes involved in the glucose sensing, metabolism, and granule exocytosis machinery (Gao et al, 2007(Gao et al, , 2010.…”

Section: Class Iii: Maturation Factorsmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

594

View full text Add to dashboard Cite

Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

show abstract

Section: Class Iii: Maturation Factorsmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

525

594

View full text Add to dashboard Cite

show abstract

“…Islet isolation was accomplished from 8-week-old mice by 100 mg of collagenase digestion (211 U/mg) followed by purification through a Histopaque gradient. Islet perifusion was carried out by placing 30 islets into a perifusion chamber (Millipore) as described previously (58). To increase the glucose secretion, we supplemented the Krebs-Ringer bicarbonate buffer (KRBH) with 50 μM of 3-isobutyl-1-methylxanthine (IBMX).…”

Section: Discussionmentioning

confidence: 99%

PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice

Iglesias¹,

Barg²,

Vallois³

et al. 2012

J. Clin. Invest.

View full text Add to dashboard Cite

PPARβ/δ protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in β cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic β cells indicated a broad repressive function of PPARβ/δ affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARβ/δ-deficient islets revealed an accelerated second phase of glucosestimulated insulin secretion. These effects in PPARβ/δ-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARβ/δ in β cell mass and insulin exocytosis, and shed a new light on PPARβ/δ metabolic action.

show abstract

“…For this we used available microarray data from adult-specific knockout mouse models of Foxa2 in islets (Gao et al 2007), Foxa2 in liver (Bochkis et al 2009), and Hnf4a in liver (Holloway et al 2008). Because no equivalent data were available from adult-specific knockout models of Pdx1, we suppressed Pdx1 using siRNAs in islets and used Tag-seq to identify genes significantly altered by Pdx1 suppression as compared to islets treated with siRNAs targeting Ppib (negative control).…”

Section: Bimodal Sites Are Functionally Activementioning

confidence: 99%

Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver

Hoffman¹,

Robertson²,

Zavaglia³

et al. 2010

Genome Res.

112

140

View full text Add to dashboard Cite

The liver and pancreas share a common origin and coexpress several transcription factors. To gain insight into the transcriptional networks regulating the function of these tissues, we globally identify binding sites for FOXA2 in adult mouse islets and liver, PDX1 in islets, and HNF4A in liver. Because most eukaryotic transcription factors bind thousands of loci, many of which are thought to be inactive, methods that can discriminate functionally active binding events are essential for the interpretation of genome-wide transcription factor binding data. To develop such a method, we also generated genome-wide H3K4me1 and H3K4me3 localization data in these tissues. By analyzing our binding and histone methylation data in combination with comprehensive gene expression data, we show that H3K4me1 enrichment profiles discriminate transcription factor occupied loci into three classes: those that are functionally active, those that are poised for activation, and those that reflect pioneer-like transcription factor activity. Furthermore, we demonstrate that the regulated presence of H3K4me1-marked nucleosomes at transcription factor occupied promoters and enhancers controls their activity, implicating both tissue-specific transcription factor binding and nucleosome remodeling complex recruitment in determining tissue-specific gene expression. Finally, we apply these approaches to generate novel insights into how FOXA2, PDX1, and HNF4A cooperate to drive islet-and liver-specific gene expression.

show abstract

Foxa2 Controls Vesicle Docking and Insulin Secretion in Mature β Cells

Cited by 80 publications

References 47 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice

Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver

Contact Info

Product

Resources

About