Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration

AbstractDespite the extensive research on molecular pathways controlling the process of regeneration in planarians and other regeneration models, little is known about the actual initiation signals necessary to induce regeneration. Previously the involvement of ROS, EGFR and MAPK/ERK has been demonstrated during planarian regeneration, however the exact interplay has not been yet described. By selectively interfering with major mediators in all three key parts (ROS, EGFR & MAPK/ERK), we were able to identify amputation/wound-induced ROS, and H2O2 specifically, as upstream cue in activating regeneration-initiation. In addition, our results demonstrate new relationships between regeneration related ROS production and MAPK/ERK activation at early regeneration stages, as well as the involvement of the EGFR-signaling pathway. In summary, our results suggest a new and more extensive signaling model with ROS, and H2O2, highlighted as upstream initiation-factor and its important functions in the downstream EGFR-MAPK/ERK pathway during planarian regeneration.

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Reactive oxygen species rescue regeneration after silencing the MAPK–ERK signaling pathway in Schmidtea mediterranea

Scientific Reports ◽

10.1038/s41598-020-79588-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

V. Jaenen ◽

S. Fraguas ◽

K. Bijnens ◽

M. Heleven ◽

T. Artois ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Signaling Pathway ◽

Reactive Oxygen ◽

Light Therapy ◽

Erk Signaling ◽

Model Organisms ◽

Ros Production ◽

Oxygen Species ◽

Planarian Regeneration ◽

Egfr Signaling Pathway

AbstractDespite extensive research on molecular pathways controlling the process of regeneration in model organisms, little is known about the actual initiation signals necessary to induce regeneration. Recently, the activation of ERK signaling has been shown to be required to initiate regeneration in planarians. However, how ERK signaling is activated remains unknown. Reactive Oxygen Species (ROS) are well-known early signals necessary for regeneration in several models, including planarians. Still, the probable interplay between ROS and MAPK/ERK has not yet been described. Here, by interfering with major mediators (ROS, EGFR and MAPK/ERK), we were able to identify wound-induced ROS, and specifically H2O2, as upstream cues in the activation of regeneration. Our data demonstrate new relationships between regeneration-related ROS production and MAPK/ERK activation at the earliest regeneration stages, as well as the involvement of the EGFR-signaling pathway. Our results suggest that (1) ROS and/or H2O2 have the potential to rescue regeneration after MEK-inhibition, either by H2O2-treatment or light therapy, (2) ROS and/or H2O2 are required for the activation of MAPK/ERK signaling pathway, (3) the EGFR pathway can mediate ROS production and the activation of MAPK/ERK during planarian regeneration.

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The role of the EGFR signaling pathway in stem cell differentiation during planarian regeneration and homeostasis

Seminars in Cell and Developmental Biology ◽

10.1016/j.semcdb.2018.05.011 ◽

2019 ◽

Vol 87 ◽

pp. 45-57 ◽

Cited By ~ 3

Author(s):

Sara Barberán ◽

Francesc Cebrià

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Signaling Pathway ◽

Stem Cell Differentiation ◽

Egfr Signaling ◽

Planarian Regeneration ◽

Egfr Signaling Pathway

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The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis

Development ◽

10.1242/dev.131995 ◽

2016 ◽

Vol 143 (12) ◽

pp. 2089-2102 ◽

Cited By ~ 24

Author(s):

Sara Barberán ◽

Susanna Fraguas ◽

Francesc Cebrià

Keyword(s):

Signaling Pathway ◽

Egfr Signaling ◽

Planarian Regeneration ◽

Egfr Signaling Pathway

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Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos

Scientific Reports ◽

10.1038/s41598-019-55203-w ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Yildiz Koca ◽

Benjamin E. Housden ◽

William J. Gault ◽

Sarah J. Bray ◽

Marek Mlodzik

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Planar Cell Polarity ◽

Egf Receptor ◽

Control Cell ◽

Loss Of Function ◽

Egfr Signaling ◽

Specific Expression ◽

Egfr Signaling Pathway ◽

Ommatidial Rotation

AbstractIn all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. In Drosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles of Notch, belonging to the Nfacet class, reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription of argos (aos), an inhibitory ligand to the epidermal growth factor receptor (EGFR), to fine-tune the activity of EGFR signaling. Consistently, the loss-of-function defects of Nfacet alleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulated aos enhancer confers R4 specific expression arguing that aos is directly regulated by Notch signaling in this context via Su(H)-Mam-dependent transcription.

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Insulin-like growth factor-I signaling is modified during chondrocyte differentiation

Journal of Endocrinology ◽

10.1677/joe.1.05873 ◽

2004 ◽

Vol 183 (3) ◽

pp. 477-486 ◽

Cited By ~ 56

Author(s):

Chanika Phornphutkul ◽

Ke-Ying Wu ◽

Xu Yang ◽

Qian Chen ◽

Philip A Gruppuso

Keyword(s):

Growth Factor ◽

Cell Line ◽

Chondrocyte Differentiation ◽

Erk Pathway ◽

Insulin Like Growth Factor ◽

Erk Activation ◽

Atdc5 Cell ◽

Factor I ◽

Proliferation And Differentiation ◽

Igf I

Insulin-like growth factor-I (IGF-I) is a critical regulator of skeletal growth. While IGF-I has been shown to be a potent chondrocyte mitogen in vitro, its role in chondrocyte differentiation is less well characterized. We chose to study the action of IGF-I on an accepted model of chondrocyte differentiation, the ATDC5 cell line. Insulin concentrations sufficiently high to interact with the IGF-I receptor are routinely used to induce ATDC5 cells to differentiate. Therefore, we first examined the ability of IGF-I to promote chondrocyte differentiation at physiological concentrations. IGF-I could induce differentiation of these cells at concentrations below 10 nM. However, increasing IGF-I concentrations were less potent at inducing differentiation. We hypothesized that mitogenic effects of IGF-I might inhibit its differentiating effects. Indeed, the extracellular-signal-regulated kinase (ERK)-pathway inhibitor PD98059 inhibited ATDC5 cell DNA synthesis while enhancing differentiation. This suggested that the ability of IGF-I to promote both proliferation and differentiation might require that its signaling be modulated through the differentiation process. We therefore compared IGF-I-mediated ERK activation in proliferating and hypertrophic chondrocytes. IGF-I potently induced ERK activation in proliferating cells, but minimal ERK response was seen in hypertrophic cells. In contrast, IGF-I-mediated Akt activation was unchanged by differentiation, indicating intact upstream IGF-I receptor signaling. Similar findings were observed in the RCJ3.1C5.18 chondrogenic cell line and in primary chick chondrocytes. We conclude that IGF-I promotes both proliferation and differentiation of chondrocytes and that the differentiation effects of IGF-I may require uncoupling of signaling to the ERK pathway.

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CG6015 controls spermatogonia transit-amplifying divisions by epidermal growth factor receptor signaling in Drosophila testes

Cell Death and Disease ◽

10.1038/s41419-021-03783-9 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Jun Yu ◽

Qianwen Zheng ◽

Zhiran Li ◽

Yunhao Wu ◽

Yangbo Fu ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Stem Cell ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Growth Factor Receptor ◽

Gene Set Enrichment Analysis ◽

Germline Stem Cell ◽

Egfr Signaling ◽

Egfr Signaling Pathway ◽

Epidermal Growth

AbstractSpermatogonia transit-amplifying (TA) divisions are crucial for the differentiation of germline stem cell daughters. However, the underlying mechanism is largely unknown. In the present study, we demonstrated that CG6015 was essential for spermatogonia TA-divisions and elongated spermatozoon development in Drosophila melanogaster. Spermatogonia deficient in CG6015 inhibited germline differentiation leading to the accumulation of undifferentiated cell populations. Transcriptome profiling using RNA sequencing indicated that CG6015 was involved in spermatogenesis, spermatid differentiation, and metabolic processes. Gene Set Enrichment Analysis (GSEA) revealed the relationship between CG6015 and the epidermal growth factor receptor (EGFR) signaling pathway. Unexpectedly, we discovered that phosphorylated extracellular regulated kinase (dpERK) signals were activated in germline stem cell (GSC)-like cells after reduction of CG6015 in spermatogonia. Moreover, Downstream of raf1 (Dsor1), a key downstream target of EGFR, mimicked the phenotype of CG6015, and germline dpERK signals were activated in spermatogonia of Dsor1 RNAi testes. Together, these findings revealed a potential regulatory mechanism of CG6015 via EGFR signaling during spermatogonia TA-divisions in Drosophila testes.

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The ERK pathway involves positive and negative regulations of HT-29 colorectal cancer cell growth by extracellular zinc

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00047.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. G1181-G1188 ◽

Cited By ~ 19

Author(s):

Ki-Sook Park ◽

Nam-Gu Lee ◽

Ki-Hoo Lee ◽

Jeong Taeg Seo ◽

Kang-Yell Choi

Keyword(s):

Colorectal Cancer ◽

Signal Transduction ◽

Cell Proliferation ◽

Cell Growth ◽

Cyclin D1 ◽

Growth Regulation ◽

Erk Pathway ◽

Differential Growth ◽

Erk Activation ◽

Ht 29

Dietary zinc is an important trace element in the body and is related to both cell proliferation and growth arrest. A recent study found that extracellular zinc-sensing receptors trigger intracellular signal transduction in HT-29 human colorectal cancer cells. However, the signaling mechanism causing this growth regulation by extracellular zinc is not clearly understood. At 10- and 100-μM levels of ZnCl2 treatment, HT-29 cell growth and proliferation increased and decreased, respectively, in a minimally serum-starved medium (MSSM). A lack of significant increase in intracellular zinc levels after zinc treatment suggested that this differential growth regulation of HT-29 cells by extracellular zinc is acquired by receptor-mediated signal transduction. Moreover, this zinc-induced growth regulation was differentially affected by PD-98059, suggesting the involvement of the ERK pathway. Transient ERK activation and subsequent cyclin D1 induction were observed on adding 10 μM ZnCl2 in MSSM in the presence of cell proliferation. On the other hand, prolonged ERK activity was observed with a subsequent increase of cyclin D1 and p21Cip/WAF1 on adding 100 μM ZnCl2 in MSSM, and this was associated with nonproliferation. Moreover, this ERK activation and cyclin D1 and p21Cip/WAF1 induction were abolished by PD-98059 pretreatment. The differential regulations of cell growth, ERK activities, and cyclin D1 and p21Cip/WAF1 inductions were also observed in serum-enriched medium containing higher zinc concentrations. Therefore, differential cell cycle regulator induction occurs by a common ERK pathway in the differential growth regulation of HT-29 cells by extracellular zinc.

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