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.
Front Genet
2019 Feb 19;10:112. doi: 10.3389/fgene.2019.00112.
Show Gene links
Show Anatomy links
Wnt Signaling Pathway Linked to Intestinal Regeneration via Evolutionary Patterns and Gene Expression in the Sea Cucumber Apostichopus japonicus.
Yuan J
,
Gao Y
,
Sun L
,
Jin S
,
Zhang X
,
Liu C
,
Li F
,
Xiang J
.
Abstract
Many echinoderms are regenerative species that exhibit exceptional regenerative capacity, and sea cucumber is a representative organism that could regenerate the whole intestine after evisceration. There are many signaling pathways participate in the regeneration process, but it is not clear which is essential for the intestinal regeneration. In this study, we performed genome-wide comprehensive analyses on these regeneration-related signaling pathways, and found the Wnt signaling pathway was one of the most conservative pathways among regenerative species. Additionally, among these signaling pathways, we found that the Wnt signaling pathway was the only one under positive selection in regenerative echinoderms, and the only one enriched by differentially expressed genes during the intestinal regeneration. Thus, it suggests both coding sequence and gene expression of the Wnt signaling pathway have been shaped by natural selection to provide the genetic architecture for intestinal regeneration. Wnt7, Fz7, and Dvl are the three positively selected genes and also happen to be three upstream genes in the Wnt signaling pathway. They are all significantly upregulated at the early stages of regeneration, which may contribute significantly to the early activation of Wnt signaling and the initiation of intestinal regeneration. Expression knockdown of Wnt7 and Dvl by RNA interference significantly inhibit intestinal extension, implying that they are essential for intestinal regeneration. As an important regeneration-related gene, the downstream gene c-Myc is also conserved and highly expressed during the whole regeneration stages, which may make the Wnt/c-Myc signaling to be an important way to promote intestinal regeneration. Therefore, it is reasonable to conclude that the Wnt signaling pathway is the chosen one to play an important role in intestinal regeneration of sea cucumbers, or even in the regeneration of other echinoderms.
FIGURE 1. Methods of identifying key pathways and genes in regeneration. The methods combined the results of gene gain/gene loss analysis, positive selection analysis, and DGE analysis.
FIGURE 2. Comparative analysis of genes in regeneration-related signaling pathways of regenerative animals. The comparative analysis are performed on seven regeneration-related signaling pathways of six species. The genes present in genomes are markered in green background, and the genes absent in genomes are markered in other colors according to the legends.
FIGURE 3. Wnt gene family in echinoderms. (A) Phylogenetic tree of the Wnt gene family of three echinoderms and Saccoglossus kowalevskii. The phylogenetic tree is constructed using the maximum likelihood (ML) method with 1000 bootstraps and Bayesian inference (BI). Yellow circles indicate the support values of ML analysis larger than 80%. The support values of BI analysis are displayed beside each node. (B) Comparison of Wnt gene family members across echinoderms and S. kowalevskii. Empty indicate the loss of particular Wnt genes, and overlapping boxes represent duplicated Wnt genes.
FIGURE 4. Differential expression analysis of genes during intestinal regeneration. (A) Expression profiles of the DEGs at different intestinal regeneration time points: 0 (C), 3 day (3d), 5 day (5d), 7 day (7d), 14 day (14d), 21 day (21d). DEGs are divided into five groups that significantly expressed at 3d (3d versus C), 5d (5d versus 3d), 7d (7d versus 5d), 14d (14d versus 7d), and 21d (21d versus 14d). (B) Significantly enriched pathways of DEGs that significantly upregulated at 3d. RichFactor is the ratio of the number of DEGs in this pathway term to the number of all genes in this pathway term.
FIGURE 5. Differential expression analysis of Wnt signaling pathway genes. (A) Expression profiles of the DEGs at different intestinal regeneration time points: 0 (C), 3 day (3d), 5 day (5d), 7 day (7d), 14 day (14d), 21 day (21d). Genes with different colors are correspondent to the color of genes in the plot B. (B) Genes involved in Wnt signaling pathway. Genes from upstream to downstream of the Wnt signaling pathway are in different color.
Agata,
Survey of the differences between regenerative and non-regenerative animals.
2012, Pubmed
Agata,
Survey of the differences between regenerative and non-regenerative animals.
2012,
Pubmed
Ashton,
Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling.
2010,
Pubmed
Balabaud,
The role of hepatic stellate cells in liver regeneration.
2004,
Pubmed
Bannister,
Afuni, a novel transforming growth factor-beta gene is involved in arm regeneration by the brittle star Amphiura filiformis.
2005,
Pubmed
,
Echinobase
Brockes,
Comparative aspects of animal regeneration.
2008,
Pubmed
Burdon,
Signaling mechanisms regulating self-renewal and differentiation of pluripotent embryonic stem cells.
1999,
Pubmed
Cai,
The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program.
2010,
Pubmed
Candelaria,
Contribution of mesenterial muscle dedifferentiation to intestine regeneration in the sea cucumber Holothuria glaberrima.
2006,
Pubmed
,
Echinobase
Conant,
Regeneration in the African lungfish, Protopterus. 3. Regeneration during fasting and estivation.
1973,
Pubmed
Darriba,
jModelTest 2: more models, new heuristics and parallel computing.
2012,
Pubmed
Delorme,
Scar-free wound healing and regeneration following tail loss in the leopard gecko, Eublepharis macularius.
2012,
Pubmed
Dolmatov,
Post-autotomy regeneration of respiratory trees in the holothurian Apostichopus japonicus (Holothuroidea, Aspidochirotida).
2009,
Pubmed
,
Echinobase
Dong,
A Conditioned Medium of Umbilical Cord Mesenchymal Stem Cells Overexpressing Wnt7a Promotes Wound Repair and Regeneration of Hair Follicles in Mice.
2017,
Pubmed
Edgar,
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
2004,
Pubmed
Espada,
Wnt signalling and cancer stem cells.
2009,
Pubmed
Evan,
Induction of apoptosis in fibroblasts by c-myc protein.
1992,
Pubmed
Evangelista,
The hedgehog signaling pathway in cancer.
2006,
Pubmed
Finn,
The Pfam protein families database: towards a more sustainable future.
2016,
Pubmed
García-Arrarás,
Cellular mechanisms of intestine regeneration in the sea cucumber, Holothuria glaberrima Selenka (Holothuroidea:Echinodermata).
1998,
Pubmed
,
Echinobase
Girich,
Wnt and frizzled expression during regeneration of internal organs in the holothurian Eupentacta fraudatrix.
2017,
Pubmed
,
Echinobase
Guindon,
A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood.
2003,
Pubmed
Hall,
The crown-of-thorns starfish genome as a guide for biocontrol of this coral reef pest.
2017,
Pubmed
,
Echinobase
Heatfield,
Ultrastructural studies of regenerating spines of the sea urchin Strongylocentrotus purpuratus. II. Cell types with spherules.
1975,
Pubmed
,
Echinobase
Karhadkar,
Hedgehog signalling in prostate regeneration, neoplasia and metastasis.
2004,
Pubmed
Kuang,
Asymmetric self-renewal and commitment of satellite stem cells in muscle.
2007,
Pubmed
Kuhnert,
Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1.
2004,
Pubmed
Letunic,
SMART: recent updates, new developments and status in 2015.
2015,
Pubmed
Li,
Identification and expression characterization of WntA during intestinal regeneration in the sea cucumber Apostichopus japonicus.
2017,
Pubmed
,
Echinobase
Li,
OrthoMCL: identification of ortholog groups for eukaryotic genomes.
2003,
Pubmed
Li,
Pathogen-origin horizontally transferred genes contribute to the evolution of Lepidopteran insects.
2011,
Pubmed
Liu,
Gekko japonicus genome reveals evolution of adhesive toe pads and tail regeneration.
2015,
Pubmed
Lu,
Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells.
2011,
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
Mishra,
The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer.
2005,
Pubmed
Mo,
The Hippo signaling pathway in stem cell biology and cancer.
2014,
Pubmed
Nostro,
Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells.
2011,
Pubmed
Ochoa,
Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice.
2010,
Pubmed
Okita,
Intracellular signaling pathways regulating pluripotency of embryonic stem cells.
2006,
Pubmed
Ortiz-Pineda,
Gene expression profiling of intestinal regeneration in the sea cucumber.
2009,
Pubmed
,
Echinobase
Patruno,
Anbmp2/4 is a new member of the transforming growth factor-beta superfamily isolated from a crinoid and involved in regeneration.
2003,
Pubmed
Reya,
Wnt signalling in stem cells and cancer.
2005,
Pubmed
Robert,
A comprehensive survey of wnt and frizzled expression in the sea urchin Paracentrotus lividus.
2014,
Pubmed
,
Echinobase
Ronquist,
MrBayes 3: Bayesian phylogenetic inference under mixed models.
2003,
Pubmed
Rubilar,
Timing of fission in the starfish Allostichaster capensis (Echinodermata: Asteroidea) in laboratory.
2005,
Pubmed
,
Echinobase
Shibata,
Staging of regeneration process of an arm of the feather star Oxycomanthus japonicus focusing on the oral-aboral boundary.
2010,
Pubmed
,
Echinobase
Sun,
Large scale gene expression profiling during intestine and body wall regeneration in the sea cucumber Apostichopus japonicus.
2011,
Pubmed
,
Echinobase
Sun,
Cloning and expression analysis of Wnt6 and Hox6 during intestinal regeneration in the sea cucumber Apostichopus japonicus.
2013,
Pubmed
,
Echinobase
Sun,
iTRAQ reveals proteomic changes during intestine regeneration in the sea cucumber Apostichopus japonicus.
2017,
Pubmed
,
Echinobase
Talavera,
Improvement of phylogenies after removing divergent and ambiguously aligned blocks from protein sequence alignments.
2007,
Pubmed
Thompson,
Multiple sequence alignment using ClustalW and ClustalX.
2002,
Pubmed
Trapnell,
Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks.
2012,
Pubmed
Trapnell,
TopHat: discovering splice junctions with RNA-Seq.
2009,
Pubmed
Trompouki,
Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration.
2011,
Pubmed
Wilson,
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
2004,
Pubmed
Yang,
Synonymous and nonsynonymous rate variation in nuclear genes of mammals.
1998,
Pubmed
Yang,
Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution.
1998,
Pubmed
Yu,
Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer.
2015,
Pubmed
Zhang,
Wnt/β-catenin signaling pathway upregulates c-Myc expression to promote cell proliferation of P19 teratocarcinoma cells.
2012,
Pubmed
Zhang,
The sea cucumber genome provides insights into morphological evolution and visceral regeneration.
2017,
Pubmed
,
Echinobase
Zhao,
The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal.
2011,
Pubmed
Zhu,
Horizontal gene transfer in silkworm, Bombyx mori.
2011,
Pubmed
von Maltzahn,
Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle.
2011,
Pubmed
