The Edges of Pancreatic Islet β Cells Constitute Adhesive and Signaling Microdomains

Geron, Erez; Boura‐Halfon, Sigalit; Schejter, Eyal D.; Shilo, Ben‐Zion

doi:10.1016/j.celrep.2014.12.031

Cited by 59 publications

(63 citation statements)

References 32 publications

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“…We observed that the cell-cell interface between adjacent beta cells is characterized by a dense cortical actin network (Fig. 5f), which is implicated in the recruitment and docking of secretory granules41. We also captured three-dimensional (3D) super-resolution images of human islet beta cells immunostained for insulin using the alternative super-resolution method of structured illumination microscopy (SIM)43 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Advances in pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation

Phelps

Cianciaruso

Santo‐Domingo

et al. 2017

Sci Rep

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A robust and reproducible method for culturing monolayers of adherent and well-spread primary islet cells on glass coverslips is required for detailed imaging studies by super-resolution and live-cell microscopy. Guided by an observation that dispersed islet cells spread and adhere well on glass surfaces in neuronal co-culture and form a monolayer of connected cells, we demonstrate that in the absence of neurons, well-defined surface coatings combined with components of neuronal culture media collectively support robust attachment and growth of primary human or rat islet cells as monolayers on glass surfaces. The islet cell monolayer cultures on glass stably maintain distinct mono-hormonal insulin+, glucagon+, somatostatin+ and PP+ cells and glucose-responsive synchronized calcium signaling as well as expression of the transcription factors Pdx-1 and NKX-6.1 in beta cells. This technical advance enabled detailed observation of sub-cellular processes in primary human and rat beta cells by super-resolution microscopy. The protocol is envisaged to have broad applicability to sophisticated analyses of pancreatic islet cells that reveal new biological insights, as demonstrated by the identification of an in vitro protocol that markedly increases proliferation of primary beta cells and is associated with a reduction in ciliated, ostensibly proliferation-suppressed beta cells.

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Section: Resultsmentioning

confidence: 99%

Advances in pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation

Phelps

Cianciaruso

Santo‐Domingo

et al. 2017

Sci Rep

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“…Although pancreatic β-cells do not display the typical epithelial polarity, they concentrate F-actin and exocytic machinery, including Ca v 1.3, at cell edges and particularly at cell vertexes facing blood vessels within islets (Geron et al, 2015). This polarity seems to be functionally important, because exocytosis in islets preferentially occurs in the vicinity of vessels, around which β-cells form rosettes (Takahashi et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa

Fan

Matsunaga

Wang

et al. 2017

eLife

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Exophilin-8 has been reported to play a role in anchoring secretory granules within the actin cortex, due to its direct binding activities to Rab27 on the granule membrane and to F-actin and its motor protein, myosin-Va. Here, we show that exophilin-8 accumulates granules in the cortical F-actin network not by direct interaction with myosin-Va, but by indirect interaction with a specific form of myosin-VIIa through its previously unknown binding partner, RIM-BP2. RIM-BP2 also associates with exocytic machinery, Cav1.3, RIM, and Munc13-1. Disruption of the exophilin-8–RIM-BP2–myosin-VIIa complex by ablation or knockdown of each component markedly decreases both the peripheral accumulation and exocytosis of granules. Furthermore, exophilin-8-null mouse pancreatic islets lose polarized granule localization at the β-cell periphery and exhibit impaired insulin secretion. This newly identified complex acts as a physical and functional scaffold and provides a mechanism supporting a releasable pool of granules within the F-actin network beneath the plasma membrane.DOI: http://dx.doi.org/10.7554/eLife.26174.001

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“…There is evidence to suggest that similar transcellular interactions help direct the formation of the insulin exocytic machinery. This evidence includes the dependence of ␤-cell function and maturation on contact between ␤-cells as well as the tendency for exocytic complexes to form beneath the ␤-cell plasma membrane at sites where such cell-to-cell contact occurs (12,16,27).…”

Section: Discussionmentioning

confidence: 99%

“…This contact gives rise to transcellular protein interactions that drive the maturation and help regulate the function of the insulin secretory machinery (19,27,31,40,50). Consistent with an essential role of interactions between ␤-cells, insulin exocytic complexes assemble under the plasma membrane at sites of ␤-cell-to-␤-cell contact (16). Identifying the transcellular protein interactions that mediate the effects of ␤-cell-to-␤-cell contact and help guide assembly and functioning of the insulin secretory machinery is crucial for understanding how contact between ␤-cells promotes functional maturation and helps to control insulin secretion.…”

mentioning

confidence: 97%

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

Zhang

Caldwell

Mirbolooki

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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N, Chessler SD. Extracellular CADM1 interactions influence insulin secretion by rat and human islet ␤-cells and promote clustering of syntaxin-1. Am J Physiol Endocrinol Metab 310: E874 -E885, 2016. First published April 12, 2016 doi:10.1152/ajpendo.00318.2015-Contact between ␤-cells is necessary for their normal function. Identification of the proteins mediating the effects of ␤-cell-to-␤-cell contact is a necessary step toward gaining a full understanding of the determinants of ␤-cell function and insulin secretion. The secretory machinery of the ␤-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the transcellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such transcellular interactions, important for both synaptic and ␤-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here, we tested the role of another synaptic cleft protein, CADM1, in insulinoma cells and in rat and human islet ␤-cells. We found that CADM1 is a predominant CADM isoform in ␤-cells. In INS-1 cells and primary ␤-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we found that CADM1 also influences insulin secretion in a transcellular manner. We asked whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on ␤-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing ␤-cell dysfunction in diabetes.cell adhesion molecule 1; SynCam; pancreatic islet; insulin secretion

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The Edges of Pancreatic Islet β Cells Constitute Adhesive and Signaling Microdomains

Cited by 59 publications

References 32 publications

Advances in pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation

Advances in pancreatic islet monolayer culture on glass surfaces enable super-resolution microscopy and insights into beta cell ciliogenesis and proliferation

Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa

Extracellular CADM1 interactions influence insulin secretion by rat and human islet β-cells and promote clustering of syntaxin-1

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