Analysis of the conserved neurotrophic factor MANF in the Drosophila adult brain

Stratoulias, Vassilis; Heino, Tapio I.

doi:10.1016/j.gep.2015.04.002

Cited by 17 publications

(22 citation statements)

References 31 publications

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“…To verify the specificity of DmManf overexpression on the observed genetic interactions, we used UAS-mCD8-GFP construct as a control for overexpression of a protein processed in the ER. In our previous and current work, we have never detected any obvious phenotypes in flies overexpressing DmManf with a variety of GAL4 drivers in wild type background ( Fig 2B and S2A Fig , [ 20 , 43 ]). Surprisingly, simultaneous overexpression of DmManf strongly enhanced the phenotypes caused by knockdown of Hsc3 , PEK (pancreatic eIF-2alpha kinase, homologue to human PERK), Xbp1 and sip3 (septin interacting protein 3) ( Fig 2A , these results are described in detail below).…”

Section: Resultsmentioning

confidence: 62%

“…Surprisingly, we discovered that the overexpression of DmManf led to enhanced phenotypes in flies of which a UPR-related gene was knocked down. Thus far, overexpression of DmManf with any GAL4 driver we have tested has never resulted in a detectable phenotype or altered viability ( Fig 2B , S2A Fig , [ 20 , 43 ]). According to our previous microarray analysis, DmManf overexpression led to downregulation of UPR-related genes [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

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Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

et al. 2016

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Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. ER stress activates unfolded protein response (UPR), a cellular mechanism the purpose of which is to restore ER homeostasis. Previous studies show that Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an important novel component in the regulation of UPR. In vertebrates, MANF is upregulated by ER stress and protects cells against ER stress-induced cell death. Biochemical studies have revealed an interaction between mammalian MANF and GRP78, the major ER chaperone promoting protein folding. In this study we discovered that the upregulation of MANF expression in response to drug-induced ER stress is conserved between Drosophila and mammals. Additionally, by using a genetic in vivo approach we found genetic interactions between Drosophila Manf and genes encoding for Drosophila homologues of GRP78, PERK and XBP1, the key components of UPR. Our data suggest a role for Manf in the regulation of Drosophila UPR.

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Section: Resultsmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

et al. 2016

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“…Inactivation of the Manf gene in fruit flies causes defects in the formation of dopaminergic axonal bundles and decreased dopamine levels (Palgi et al, 2009). However, knock-down of neuronal DmManf does not affect the dopamine system in adult flies (Stratoulias and Heino, 2015). In zebrafish, knock-down of Manf results in a decreased number of dopamine neurons without phenotypic defects (Chen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a

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“…Subsequent studies indicated that MANF is induced and secreted in response to experimental endoplasmic reticulum (ER) stress in vitro and in vivo (3)(4)(5)(6). MANF has a protective role under physiological and pathophysiological conditions, including in neurodegenerative diseases, ischemic heart disease, diabetes mellitus, chondrodysplasia and polycystic ovary syndrome (4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Further studies have suggested that MANF protects against various forms of ER stress-induced cell damage via its C-terminal domain.…”

Section: Introductionmentioning

confidence: 99%

Activator protein‑1 is a novel regulator of mesencephalic astrocyte‑derived neurotrophic factor transcription

et al. 2018

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum stress-inducible protein, which has been suggested to be upregulated in inflammatory diseases; however, how inflammation regulates its transcription remains unclear. Activator protein-1 (AP-1), which is a transcription factor complex composed of c-Fos and c-Jun, is activated during the inflammatory process. The present study aimed to investigate whether the AP-1 complex regulates MANF transcription. The results of a luciferase reporter assay revealed that one of three putative AP-1 binding sites in the MANF promoter region is essential for enhancement of MANF transcription. Mechanistically, AP-1 was revealed to directly bind to the promoter region of the MANF gene by chromatin immunoprecipitation assay. Furthermore, MANF was strongly expressed in the liver tissues of patients with hepatitis B virus (HBV) infection, compared with in normal liver tissues from patients with hepatic hemangioma. Furthermore, c-Fos and c-Jun were also upregulated in the nuclei of hepatocytes from patients with HBV infection. In mice treated with carbon tetrachloride, the expression patterns of MANF, c-Fos and c-Jun were similar to those in patients with HBV. These results suggested that the AP-1 complex may be a novel regulator of MANF transcription, which may be involved in liver inflammation and fibrosis.

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Analysis of the conserved neurotrophic factor MANF in the Drosophila adult brain

Cited by 17 publications

References 31 publications

Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Activator protein‑1 is a novel regulator of mesencephalic astrocyte‑derived neurotrophic factor transcription

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