Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Dev Biol
2020 Feb 01;4581:12-31. doi: 10.1016/j.ydbio.2019.10.005.
Show Gene links
Show Anatomy links
Insights into intestinal regeneration signaling mechanisms.
Bello SA
,
Torres-Gutiérrez V
,
Rodríguez-Flores EJ
,
Toledo-Román EJ
,
Rodríguez N
,
Díaz-Díaz LM
,
Vázquez-Figueroa LD
,
Cuesta JM
,
Grillo-Alvarado V
,
Amador A
,
Reyes-Rivera J
,
García-Arrarás JE
.
???displayArticle.abstract???
The cellular mechanisms underlying the amazing ability of sea cucumbers to regenerate their autotomized intestines have been widely described by us and others. However, the signaling pathways that control these mechanisms are unknown. Previous studies have shown that Wnt homologs are upregulated during early intestinal regenerative stages, suggesting that the Wnt/β-catenin pathway is active during this process. Here, we used small molecules, putative disruptors of the Wnt pathway, to determine the potential role of the canonical Wnt pathway on intestine regeneration in the sea cucumber Holothuria glaberrima. We evaluated their effects in vivo by using histological analyses for cell dedifferentiation, cell proliferation and apoptosis. We found that iCRT14, an alleged Wnt pathway inhibitor, decreased the size of the regenerating intestine, while LiCl, a presumed Wnt pathway activator, increased its size. The possible cellular mechanisms by which signaling pathway disruptors affect the gut rudiment size were further studied in vitro, using cultures of tissue explants and additional pharmacological agents. Among the tested signaling activators, those that act through GSK-3 inhibition, LiCl, 1-Azakenpaullone, and CHIR99021 were found to increase muscle cell dedifferentiation, while the inhibitor iCRT14 blocked cell dedifferentiation. Differently, cell proliferation was reduced by all GSK-3 inhibitors, as well as by iCRT14 and C59, which interferes with Wnt ligand secretion. The in vivo temporal and spatial pattern of β-catenin activity was determined using an antibody against phosphorylated β-catenin and shown to correlate with cell proliferative activity. In vitro treatment using C59 decreased the number of cells immunostained for nuclear phosphorylated β-catenin. Our results showed that the cell dedifferentiation observed during intestinal regeneration can be decoupled from the cell proliferation event and that these cellular processes can be modulated by particular signaling pathway inhibitors and activators. These results open the door for future studies where the cellular signaling pathways involved at each regeneration stage can be determined.
Adell,
Planarian GSK3s are involved in neural regeneration.
2008, Pubmed
Adell,
Planarian GSK3s are involved in neural regeneration.
2008,
Pubmed
Bello,
Primary cell cultures of regenerating holothurian tissues.
2015,
Pubmed
,
Echinobase
Bodine,
Wnt signaling control of bone cell apoptosis.
2008,
Pubmed
Broun,
Formation of the head organizer in hydra involves the canonical Wnt pathway.
2005,
Pubmed
Candelaria,
Contribution of mesenterial muscle dedifferentiation to intestine regeneration in the sea cucumber Holothuria glaberrima.
2006,
Pubmed
,
Echinobase
Charlier,
Restriction of spontaneous and prednisolone-induced leptin production to dedifferentiated state in human hip OA chondrocytes: role of Smad1 and β-catenin activation.
2016,
Pubmed
Chera,
Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration.
2009,
Pubmed
Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed
Cohen,
GSK3 inhibitors: development and therapeutic potential.
2004,
Pubmed
Cormier,
Recent advances in understanding the cellular roles of GSK-3.
2017,
Pubmed
D'Uva,
ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation.
2015,
Pubmed
Devotta,
Dkk2 promotes neural crest specification by activating Wnt/β-catenin signaling in a GSK3β independent manner.
2018,
Pubmed
Dolmatov,
Muscle regeneration in holothurians.
2001,
Pubmed
,
Echinobase
Eldar-Finkelman,
GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS.
2011,
Pubmed
Famili,
High Levels of Canonical Wnt Signaling Lead to Loss of Stemness and Increased Differentiation in Hematopoietic Stem Cells.
2016,
Pubmed
Frismantiene,
T-cadherin promotes vascular smooth muscle cell dedifferentiation via a GSK3β-inactivation dependent mechanism.
2016,
Pubmed
García-Arrarás,
Holothurians as a Model System to Study Regeneration.
2018,
Pubmed
,
Echinobase
García-Arrarás,
Cellular mechanisms of intestine regeneration in the sea cucumber, Holothuria glaberrima Selenka (Holothuroidea:Echinodermata).
1998,
Pubmed
,
Echinobase
García-Arrarás,
The mesentery as the epicenter for intestinal regeneration.
2019,
Pubmed
,
Echinobase
García-Arrarás,
Cell dedifferentiation and epithelial to mesenchymal transitions during intestinal regeneration in H. glaberrima.
2011,
Pubmed
,
Echinobase
García-Arrarás,
Echinoderms: potential model systems for studies on muscle regeneration.
2010,
Pubmed
,
Echinobase
Girich,
Wnt and frizzled expression during regeneration of internal organs in the holothurian Eupentacta fraudatrix.
2017,
Pubmed
,
Echinobase
Gonsalves,
An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway.
2011,
Pubmed
Gufler,
β-Catenin acts in a position-independent regeneration response in the simple eumetazoan Hydra.
2018,
Pubmed
Gurley,
Beta-catenin defines head versus tail identity during planarian regeneration and homeostasis.
2008,
Pubmed
Gwak,
Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation.
2012,
Pubmed
Hiyama,
Effects of a glycogen synthase kinase-3β inhibitor (LiCl) on c-myc protein in intervertebral disc cells.
2011,
Pubmed
Huang,
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
2009,
Pubmed
Jope,
Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes.
2003,
Pubmed
Jope,
The glamour and gloom of glycogen synthase kinase-3.
2004,
Pubmed
Kaufmann,
LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells.
2011,
Pubmed
Kim,
Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1.
2006,
Pubmed
Klein,
A molecular mechanism for the effect of lithium on development.
1996,
Pubmed
Komiya,
Wnt signal transduction pathways.
2008,
Pubmed
Kunick,
1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.
2004,
Pubmed
Li,
WNT/β-catenin-signaling pathway stimulates the proliferation of cultured adult human Sertoli cells via upregulation of C-myc expression.
2012,
Pubmed
Logan,
Nuclear beta-catenin is required to specify vegetal cell fates in the sea urchin embryo.
1999,
Pubmed
,
Echinobase
Mao,
Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells.
2001,
Pubmed
Mashanov,
Visceral regeneration in a sea cucumber involves extensive expression of survivin and mortalin homologs in the mesothelium.
2010,
Pubmed
,
Echinobase
Mashanov,
Gut regeneration in holothurians: a snapshot of recent developments.
2011,
Pubmed
,
Echinobase
Mashanov,
Expression of Wnt9, TCTP, and Bmp1/Tll in sea cucumber visceral regeneration.
2012,
Pubmed
,
Echinobase
Meyers,
β-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina.
2012,
Pubmed
Monje,
Schwann cell dedifferentiation is independent of mitogenic signaling and uncoupled to proliferation: role of cAMP and JNK in the maintenance of the differentiated state.
2010,
Pubmed
Murray,
Myogenesis during holothurian intestinal regeneration.
2004,
Pubmed
,
Echinobase
Naujok,
Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors.
2014,
Pubmed
Neth,
Wnt signaling regulates the invasion capacity of human mesenchymal stem cells.
2006,
Pubmed
Ono,
Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth.
2014,
Pubmed
Ortiz-Pineda,
Gene expression profiling of intestinal regeneration in the sea cucumber.
2009,
Pubmed
,
Echinobase
Osakada,
Wnt signaling promotes regeneration in the retina of adult mammals.
2007,
Pubmed
Pardo,
Opposed effects of lithium on the MEK-ERK pathway in neural cells: inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms.
2003,
Pubmed
Pasten,
Characterization of proteolytic activities during intestinal regeneration of the sea cucumber, Holothuria glaberrima.
2012,
Pubmed
,
Echinobase
Phiel,
Molecular targets of lithium action.
2001,
Pubmed
Proffitt,
Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.
2013,
Pubmed
Ramachandran,
Ascl1a/Dkk/beta-catenin signaling pathway is necessary and glycogen synthase kinase-3beta inhibition is sufficient for zebrafish retina regeneration.
2011,
Pubmed
Rhee,
Cables links Robo-bound Abl kinase to N-cadherin-bound beta-catenin to mediate Slit-induced modulation of adhesion and transcription.
2007,
Pubmed
Rudolf,
β-Catenin Activation in Muscle Progenitor Cells Regulates Tissue Repair.
2016,
Pubmed
Schacher,
Neurite regeneration by Aplysia neurons in dissociated cell culture: modulation by Aplysia hemolymph and the presence of the initial axonal segment.
1983,
Pubmed
Smits,
Inhibition of cell proliferation by lithium is associated with interference in cdc2 activation.
1999,
Pubmed
Srivastava,
Whole-body acoel regeneration is controlled by Wnt and Bmp-Admp signaling.
2014,
Pubmed
Stambolic,
Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells.
1996,
Pubmed
Stoick-Cooper,
Distinct Wnt signaling pathways have opposing roles in appendage regeneration.
2007,
Pubmed
Strand,
Wnt/β-catenin signaling promotes regeneration after adult zebrafish spinal cord injury.
2016,
Pubmed
Sun,
Cloning and expression analysis of Wnt6 and Hox6 during intestinal regeneration in the sea cucumber Apostichopus japonicus.
2013,
Pubmed
,
Echinobase
Tanaka,
Heads or tails: can Wnt tell which one is up?
2008,
Pubmed
Teo,
The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators.
2010,
Pubmed
Velloso,
Generation of mononucleate cells from post-mitotic myotubes proceeds in the absence of cell cycle progression.
2000,
Pubmed
Wang,
Lithium chloride inhibits vascular smooth muscle cell proliferation and migration and alleviates injury-induced neointimal hyperplasia via induction of PGC-1α.
2013,
Pubmed
Wehner,
Wnt/β-catenin signaling defines organizing centers that orchestrate growth and differentiation of the regenerating zebrafish caudal fin.
2014,
Pubmed
Whyte,
Wnt signaling and injury repair.
2012,
Pubmed
Yan,
Discovery of small molecule inhibitors of the Wnt/β-catenin signaling pathway by targeting β-catenin/Tcf4 interactions.
2017,
Pubmed
Yokoyama,
Wnt/beta-catenin signaling has an essential role in the initiation of limb regeneration.
2007,
Pubmed
Yuan,
Wnt Signaling Pathway Linked to Intestinal Regeneration via Evolutionary Patterns and Gene Expression in the Sea Cucumber Apostichopus japonicus.
2019,
Pubmed
,
Echinobase
Zhao,
Two phases of chromatin decondensation during dedifferentiation of plant cells: distinction between competence for cell fate switch and a commitment for S phase.
2001,
Pubmed
Zhou,
Potential Role of Glycogen Synthase Kinase-3β in Regulation of Myocardin Activity in Human Vascular Smooth Muscle Cells.
2016,
Pubmed
Zhu,
β-Catenin inactivation is a pre-requisite for chick retina regeneration.
2014,
Pubmed
