REST/NRSF governs the expression of dense-core vesicle gliosecretion in astrocytes

Prada, Ilaria; Marchaland, Julie; Podini, Paola; Magrassi, Lorenzo; D’Alessandro, Rosalba; Bezzi, Paola; Meldolesi, Jacopo

doi:10.1083/jcb.201010126

Cited by 61 publications

(60 citation statements)

References 67 publications

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“…REST KO acinar cells showed cellular swelling and an elevated concentration of zymogen granules, likely causing the observed improper localization into the basal surface. This phenotype is consistent with other cell types that show loss of REST increased dense-core vesicle gliosecretion 56 , and increase of REST caused a decrease in secretory granules 57 . The accumulation of granules in REST KO acini is likely from increased production rather than lack of secretion since loss of REST activity increases target gene expression, several of which are players in exocytosis machinery 58 .…”

Section: Discussionsupporting

confidence: 91%

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

et al. 2020

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Regulation of pancreas plasticity is critical for preventing injury and promoting regeneration upon tissue damage. The intricate process of pancreatic differentiation is governed by an orchestrated network of positive and negative transcription factors for appropriate gene expression. While the transcriptional repressor REST is well characterized as a silencer of neuronal genes in non-neuronal cells, the role of REST in regulating exocrine pancreas cell identity remains largely unexplored. Rest expression is increased upon injury in the mouse pancreas, such as induced acute and chronic pancreatitis and ductal adenocarcinoma. At the cellular level, Rest expression is lower in mature acinar cells compared with pancreas progenitor and ductal cells. To investigate the role of REST activity in pancreatic transdifferentiation and homeostasis, we developed a novel mouse model (Cre/REST fl/fl ) with conditional knockout (KO) of Rest expression within pancreas cells. The high Cre-mediated excision efficiency of Rest exon two KO caused decreased Rest expression and activity within the pancreas. Short-term organoid cultures of pancreatic acini to undergo acinar-to-ductal metaplasia (ADM) showed that loss of REST impedes induced ADM, while overexpression of REST increases ADM. Interestingly, REST ablation accelerated acute pancreatitis in mice treated with the cholecystokinin analog caerulein, as indicated by cellular morphology, elevated serum amylase levels and pancreatic edema. Furthermore, Cre/REST fl/fl mice were more sensitive to acute pancreatitis injury and displayed augmented tissue damage and cellular lesions. These results suggest REST has a novel protective role against pancreatic tissue damage by acting as a regulator of exocrine cell identity.

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Section: Discussionsupporting

confidence: 91%

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

et al. 2020

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“…For docking analysis, single NPY-mRFP-positive granules were counted manually and single cell area corresponding to docking surfaces (larger than 50 µm 2 ) measured. To observe exocytosis of NPY-mRFP at the single-vesicle level, we used 568 nm-TIRF illumination as described [18]. Single fusion events from NPY-mRFP granules were visually recognized and counted manually.…”

Section: Methodsmentioning

confidence: 99%

The GTPase Rab37 Participates in the Control of Insulin Exocytosis

et al. 2013

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Rab37 belongs to a subclass of Rab GTPases regulating exocytosis, including also Rab3a and Rab27a. Proteomic studies indicate that Rab37 is associated with insulin-containing large dense core granules of pancreatic β-cells. In agreement with these observations, we detected Rab37 in extracts of β-cell lines and human pancreatic islets and confirmed by confocal microscopy the localization of the GTPase on insulin-containing secretory granules. We found that, as is the case for Rab3a and Rab27a, reduction of Rab37 levels by RNA interference leads to impairment in glucose-induced insulin secretion and to a decrease in the number of granules in close apposition to the plasma membrane. Pull-down experiments revealed that, despite similar functional effects, Rab37 does not interact with known Rab3a or Rab27a effectors and is likely to operate through a different mechanism. Exposure of insulin-secreting cells to proinflammatory cytokines, fatty acids or oxidized low-density lipoproteins, mimicking physiopathological conditions that favor the development of diabetes, resulted in a decrease in Rab37 expression. Our data identify Rab37 as an additional component of the machinery governing exocytosis of β-cells and suggest that impaired expression of this GTPase may contribute to defective insulin release in pre-diabetic and diabetic conditions.

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“…4A; see Prada et al, 2011). Ahnak immunolabeling showed the marker concentrated in numerous small puncta spread throughout the cytoplasm (Fig.…”

Section: Resultsmentioning

confidence: 91%

Astrocyte stellation, a process dependent on Rac1 is sustained by the regulated exocytosis of enlargeosomes

Racchetti¹,

D’Alessandro

Meldolesi³

2011

Glia

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Cultured astrocytes exhibit a flat/epitelioid phenotype much different from the star-like phenotype of tissue astrocytes. Upon exposure to treatments that affect the small GTPase Rho and/or its effector ROCK, however, flat astrocytes undergo stellation, with restructuring of cytoskeleton and outgrowth of processes with lamellipodia, assuming a phenotype closer to that exhibited in situ. The mechanisms of this change are known only in part. Using the ROCK blocker drug Y27632, which induces rapid (tens of min), dose-dependent and reversible stellations, we focused on two specific aspects of the process: its dependence on small GTPases and the large surface expansion of the cells. Contrary to previous reports, we found stellation to be governed by the small G protein Rac1, up to disappearance of the process when Rac1 was downregulated or blocked by a specific drug. In contrast cdc42, the other G-protein often involved in phenotype changes, appeared not involved. The surface expansion concomitant to cytoskeleton restructuring, also dependent on Rac1, was found to be at least partially sustained by the exocytosis of enlargeosomes, small vesicles distinct from classical cell organelles, which are abundant in astrocytes. Exhaustion of stellation induced by repeated administrations of Y27632 correlated with the decrease of the enlargeosome pool. A whole-cell process like stellation of cultured astrocytes might be irrelevant in the brain tissue. However, local restructuring of the cytoskeleton coordinate with surface expansion, occurring at critical cell sites and sustained by mechanisms analogous to those of stellation, might be of importance in both astrocyte physiology and pathology. © 2011 Wiley Periodicals, Inc.

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REST/NRSF governs the expression of dense-core vesicle gliosecretion in astrocytes

Abstract: The REST/NRSF transcriptional repressor prevents cultured astrocytes from forming DCVs, and its variable expression in human brain cortex astrocytes may account for their functional heterogeneity.

Cited by 61 publications

References 67 publications

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

The GTPase Rab37 Participates in the Control of Insulin Exocytosis

Astrocyte stellation, a process dependent on Rac1 is sustained by the regulated exocytosis of enlargeosomes

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