The Experts below are selected from a list of 158811780 Experts worldwide ranked by ideXlab platform
Masaru Katoh - One of the best experts on this subject based on the ideXlab platform.
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Networking of WNT, FGF, Notch, BMP, and Hedgehog Signaling Pathways during Carcinogenesis
Stem Cell Reviews, 2007Co-Authors: Masaru KatohAbstract:The biological functions of some orthologs within the human genome and model-animal genomes are evolutionarily conserved, but those of others are divergent due to protein evolution and promoter evolution. Because WNT signaling molecules play key roles during embryogenesis, tissue regeneration and carcinogenesis, the author’s group has carried out a human WNT-ome project for the comprehensive characterization of human genes encoding WNT signaling molecules. From 1996 to 2002, we cloned and characterized WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT9A/WNT14, WNT9B/WNT14B, WNT10A, WNT10B, WNT11, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, FRAT1, FRAT2, NKD1, NKD2, VANGL1, RHOU/ARHU, RHOV/ARHV, GIPC2, GIPC3, FBXW11/βTRCP2, SOX17, TCF7L1/TCF3 , and established a cDNA-PCR system for snap-shot and dynamic analyses on the WNT-transcriptome. In 2003, we identified and characterized PRICKLE1, PRICKLE2, DACT1/DAPPER1, DACT2/DAPPER2, DAAM2 , and BCL9L . After completion of the human WNT-ome project, we have been working on the stem cell signaling network. WNT signals are transduced to β-catenin, NLK, NFAT, PKC, JNK and RhoA signaling cascades. FGF20, JAG1 and DKK1 are target genes of the WNT-β-catenin signaling cascade. Cross-talk of WNT and FGF signaling pathways potentiates β-catenin and NFAT signaling cascades. BMP signals induce IHH upregulation in co-operation with RUNX. Hedgehog signals induce upregulation of SFRP1, JAG2 and FOXL1 , and then FOXL1 induces BMP4 upregulation. The balance between WNT-FGF-Notch and BMP-Hedgehog signaling networks is important for the maintenance of homoestasis among stem and progenitor cells. Disruption of the stem cell signaling network results in pathological conditions, such as congenital diseases and cancer.
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Comparative genomics on Wnt3-Wnt9b gene cluster.
International journal of molecular medicine, 2005Co-Authors: Masaru KatohAbstract:WNT signals, transduced through Frizzled (FZD) receptors with extracellular WNT-binding domain and cytoplasmic Dishevelled-binding domain, are implicated in carcinogenesis and embryogenesis. WNT3-WNT9B (WNT14B) locus (17q21.31) and WNT3A-WNT9A (WNT14) locus (1q42.13) are paralogous regions within the human genome. Here, the rat Wnt3 and Wnt9b genes were identified and characterized by using bioinformatics. Wnt3 and Wnt9b genes at rat chromosome 10q32.1 were clustered in head-to-head manner with an interval of about 24 kb within AC105632.3 genome sequence. The rat Wnt3 gene, consisting of five exons, encoded a 355-aa protein with N-terminal signal peptide, 24 conserved Cys residues and two Asn-linked glycosylation sites. The rat Wnt9b gene, consisting of four exons, encoded a 359-aa protein with N-terminal signal peptide, 24 conserved Cys residues and one Asn-linked glycosylation site. The rat Wnt3 core promoter showed 80.5% nucleotide identity with human WNT3 core promoter, while rat Wnt9b core promoter showed 45.6% nucleotide identity with human WNT9B core promoter. MYB (c-Myb), ELK1, POU2F1 (OCT1), HNF4A (HNF-4), COMP1, NFYA (NF-Y) and NKX2-5 binding sites were conserved between rat Wnt3 and human WNT3 core promoters. The Wnt3-Wnt9b intergenic conserved region (IGCR), corresponding to nucleotide position 124747-125252 of AC105632.3 genome sequence, showed 85.6% nucleotide identity with human WNT3-WNT9B IGCR. GC content of rat Wnt3-Wnt9b IGCR was 59.5%. Wnt3-Wnt9b IGCR was predicted as regulatory element rather than gene because cDNA or EST derived from Wnt3-Wnt9b IGCR was not identified. This is the first report on the rat Wnt3 and Wnt9b genes as well as on comparative genomics on the Wnt3-Wnt9b gene cluster.
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Identification and characterization of rat Wnt1 and Wnt10b genes in silico
International Journal of Oncology, 2005Co-Authors: Yuriko Katoh, Masaru KatohAbstract:WNT family genes encode WNT family glycoproteins, while Frizzled (FZD) family genes encode seven-transmembrane-type receptors with extracellular WNT-binding domain and cytoplasmic Dishevelled-binding domain. WNT signaling pathway is implicated in carcinogenesis and embryogenesis. WNT1-WNT10B, WNT6-WNT10A, WNT3-WNT9B (WNT14B), WNT3A-WNT9A (WNT14) gene clusters exist within the human genome. Here, we identified and characterized rat Wnt1 and Wnt10b genes by using bioinformatics. Rat Wnt1 gene, consisting of four exons, encoded a 370-aa protein with signal peptide, 22 conserved Cys residues and four Asn-linked glycosylation sites. Rat Wnt10b gene, consisting of five exons, encoded a 389-aa protein with signal peptide, 24 conserved Cys residues and two Asn-linked glycosylation sites. Wnt1 and Wnt10b genes at rat chromosome 7q36 were clustered in head-to-head manner with an interval of about 10 kb within AC096835.4 or AC118760.4 genome sequences. Promoter region, exon 1 and 5'-part of intron 1 were conserved between rat and human Wnt1 orthologs. Intergenic conserved region (IGCR) was identified within the Wnt1-Wnt10b gene cluster. GC content of rat Wnt1-Wnt10b IGCR (nucleotide position 14962-15875 of AC096835.4 genome sequence) was 59.4%. Rat Wnt1-Wnt10b IGCR showed 92.5 and 74.4% nucleotide identity with mouse Wnt1-Wnt10b IGCR and human WNT1-WNT10B IGCR, respectively. Wnt1-Wnt10b IGCR was predicted as regulatory element rather than gene because cDNA or EST derived from Wnt1-Wnt10b IGCR was not identified. This is the first report on rat Wnt1 and Wnt10b genes as well as on Wnt1-Wnt10b IGCR.
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Expression and regulation of WNT1 in human cancer: Up-regulation of WNT1 by β-estradiol in MCF-7 cells
International Journal of Oncology, 2003Co-Authors: Masaru KatohAbstract:WNT family of secreted-type glycoproteins play key roles in carcinogenesis and embryogenesis. We have cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14 and WNT14B/WNT15 using bioinformatics and cDNA-PCR, and also reported frequent up-regulation of WNT2 in primary gastric cancer. Here, expression and regulation of WNT1 in human cancer were investigated using cDNA-PCR. WNT1 mRNA was relatively highly expressed in OKAJIMA cells (gastric cancer) and BxPC-3 cells (pancreatic cancer). Expression of WNT1 mRNA was up-regulated in 5 out of 10 cases of primary gastric cancer. Effects of beta-estradiol on expression of human WNT1 in MCF-7 cells (breast cancer) was next investigated, because mouse Wnt-1 induces mammary carcinogenesis even in estrogen receptor alpha (ERalpha) knockout mice. Expression of WNT1 mRNA was significantly up-regulated by beta-estradiol in MCF-7 cells. WNT1 was found to be one of estrogen target genes in human MCF-7 cells, which in part explains Wnt1-induced mammary carcinogenesis in ERalpha knockout mice.
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WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review)
International journal of molecular medicine, 2002Co-Authors: Masaru KatohAbstract:Abstract WNT signals are transduced to beta-catenin - TCF pathway, JNK pathway, or Ca2+-releasing pathway through WNT receptors. FRAT1, FRAT2, and PAR-1 are positive regulators of WNT - beta-catenin pathway. APC, AXIN, NKD1, NKD2, and Strabismus (STB1, STB2) are negative regulators of WNT - beta-catenin pathway. Here, biological significance of WNT3-WNT14B/WNT15 gene cluster (human chromosome 17q21) and WNT3A-WNT14 gene cluster (human chromosome 1q42) will be reviewed. Total-amino-acid identity between WNT3 and WNT3A is 84.2%, and that between WNT14 and WNT14B is 61.4%. WNT3A and WNT14B show reciprocal regulation by all-trans retinoic acid in NT2 cells and by beta-estradiol in MCF-7 cells. Exon-intron structures are well conserved between WNT3-WNT14B gene cluster and WNT3A-WNT14 gene cluster, except for the existence of an additional intron in 3'-UTR of WNT3. Capicua pseudogene and AK024248-related sequence are located within intergenic region of human WNT3A-WNT14 gene cluster, but not within intergenic regions of human WNT3-WNT14B gene cluster and mouse WNT3A-Wnt14 gene cluster. Integration of mouse mammary tumor virus (MMTV) into mouse Wnt3-Wnt14b gene cluster leads to carcinogenesis. Because these WNT gene clusters might be fragile sites in the human genome, implication of WNT3 or WNT3A in cancer as well as implication of WNT14 or WNT14B in connective tissue disease and congenital joint malformation should be elucidated in the future. WNT3, WNT3A, WNT14, and WNT14B might be applicable to tissue engineering of neuron and joint in the field of regenerative medicine, and as an early diagnostic marker in the field of clinical oncology.
Akira Kikuchi - One of the best experts on this subject based on the ideXlab platform.
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Apical secretion of Wnt1 in polarized epithelial cells is regulated by exocyst-mediated trafficking.
The Journal of Biochemistry, 2017Co-Authors: Hideki Yamamoto, Akira Sato, Akira KikuchiAbstract:Wnts are glycosylated proteins secreted from various cell types including mesenchymal, hematopoietic and epithelial cells. Directional secretion of Wnts in polarized epithelial cells is unique; Wnt11 is secreted apically, whereas Wnt5a and WNT3A are secreted basolaterally. Here, we found that Wnt1 is equivalently secreted both apically and basolaterally in MDCK cells. Wnt1 was modified with a complex- or hybrid-type glycan at Asn29 and Asn359 and the high-mannose- or hybrid-type glycan at Asn316. Although glycosylation of Wnt11 at the N-terminal site was shown to be essential for its apical secretion, glycosylation of Asn29 of Wnt1 was not required. Instead, the apical secretion of Wnt1 was inhibited by knockdown of Sec6 and Sec8, suggesting that Wnt1 is secreted apically via exocyst-mediated transport. Basolateral secretion of Wnt1 was mediated by clathrin and AP-1, in mechanism similar to that used by Wnt5a and WNT3A. Although Wingless was reported to be transcytosed to the basolateral region in the Drosophila wing disc, transcytosis was not involved in the basolateral secretion of Wnt1. Thus, the polarized secretion of Wnt1 is regulated by different mechanisms than other Wnts.
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Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling.
Journal of cell science, 2012Co-Authors: Hiroshi Sakane, Shinji Matsumoto, Akira Sato, Hideki Yamamoto, Akira KikuchiAbstract:Glypicans are members of the heparan sulfate proteoglycans (HSPGs) and are involved in various growth factor signaling mechanisms. Although HSPGs affect the β-catenin-dependent and -independent pathways of Wnt signaling, how they regulate distinct Wnt pathways is not clear. It has been suggested that the β-catenin-dependent pathway is initiated through receptor endocytosis in lipid raft microdomains and the independent pathway is activated through receptor endocytosis in non-lipid raft microdomains. Here, evidence is presented that glypican-4 (GPC4) is localized to both membrane microdomains and that the localization affects its ability to regulate distinct Wnt pathways. GPC4 bound to WNT3A and Wnt5a, which activate the β-catenin-dependent and -independent pathways, respectively, and colocalized with Wnts on the cell surface. LRP6, one of WNT3A coreceptors, was present in lipid raft microdomains, whereas Ror2, one of Wnt5a coreceptors, was localized to non-lipid raft microdomains. Expression of GPC4 enhanced the WNT3A-dependent β-catenin pathway and the Wnt5a-dependent β-catenin-independent pathway, and knockdown of GPC4 suppressed both pathways. A GPC4 mutant that was localized to only non-lipid raft microdomains inhibited the β-catenin-dependent pathway but enhanced the β-catenin-independent pathway. These results suggest that GPC4 concentrates WNT3A and Wnt5a to the vicinity of their specific receptors in different membrane microdomains, thereby regulating distinct Wnt signaling.
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wnt5a regulates distinct signalling pathways by binding to frizzled2
The EMBO Journal, 2010Co-Authors: Akira Sato, Hirofumi Koyama, Hiroshi Sakane, Akira Kikuchi, Hideki YamamotoAbstract:Wnt5a regulates multiple intracellular signalling cascades, but how Wnt5a determines the specificity of these pathways is not well understood. This study examined whether the internalization of Wnt receptors affects the ability of Wnt5a to regulate its signalling pathways. Wnt5a activated Rac in the β-catenin-independent pathway, and Frizzled2 (Fz2) and Ror1 or Ror2 were required for this action. Fz2 was internalized through a clathrin-mediated route in response to Wnt5a, and inhibition of clathrin-dependent internalization suppressed the ability of Wnt5a to activate Rac. As another action of Wnt5a, it inhibited WNT3A-dependent lipoprotein receptor-related protein 6 (LRP6) phosphorylation and β-catenin accumulation. WNT3A-dependent phosphorylation of LRP6 was enhanced in Wnt5a knockout embryonic fibroblasts. Fz2 was also required for the WNT3A-dependent accumulation of β-catenin, and Wnt5a competed with WNT3A for binding to Fz2 in vitro and in intact cells, thereby inhibiting the β-catenin pathway. This inhibitory action of Wnt5a was not affected by the impairment of clathrin-dependent internalization. These results suggest that Wnt5a regulates distinct pathways through receptor internalization-dependent and -independent mechanisms.
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Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2
Genes to cells : devoted to molecular & cellular mechanisms, 2007Co-Authors: Hiroyuki Yamamoto, Michiru Nishita, Akira Kikuchi, Kan Yoo, Yasuhiro MinamiAbstract:The receptor tyrosine kinase Ror2 plays important roles in mediating non-canonical Wnt5a signaling by activating the Wnt–JNK pathway and inhibiting the β-catenin–TCF pathway. It has been shown that Ror2 is phosphorylated and activated by casein kinase Iɛ when both molecules are over-expressed in cultured cells. However, it remains unknown whether or not Ror2 is phosphorylated upon Wnt5a stimulation. Here we show that Ror2 is phosphorylated on serine/threonine residues upon stimulation of cultured cells, expressing Ror2 endogenously, with Wnt5a, but not WNT3A. It was found that treatment of cells with glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl and SB216763) or small interfering RNAs (siRNAs) for GSK-3 (mainly GSK-3α) can inhibit Wnt5a-induced phosphorylation of Ror2. Immunoprecipitated Ror2 can also be phosphorylated by purified GSK-3α or GSK-3βin vitro, and ectopic co-expression of Ror2 and GSK-3 (mainly GSK-3α) in cultured cells results in Ror2 phosphorylation, irrespective of Wnt5a, that is sensitive to SB216763. These results indicate that GSK-3 is involved in Wnt5a-induced phosphorylation of Ror2. Moreover, it was found that Wnt5a-induced cell migration can be inhibited by SB216763 or by siRNA-mediated suppression of GSK-3α (and GSK-3β) expression, further emphasizing the role(s) of GSK-3 in Wnt5a-induced signaling.
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filopodia formation mediated by receptor tyrosine kinase ror2 is required for wnt5a induced cell migration
Journal of Cell Biology, 2006Co-Authors: Michiru Nishita, Akira Nomachi, Yasutaka Ohta, Shinji Takada, Nagako Sougawa, Akira Kikuchi, Shuichi Kani, Yasuhiro MinamiAbstract:The receptor tyrosine kinase Ror2 plays important roles in developmental morphogenesis. It has recently been shown that Ror2 mediates Wnt5a-induced noncanonical Wnt signaling by activating the Wnt–JNK pathway and inhibiting the β-catenin–TCF pathway. However, the function of Ror2 in noncanonical Wnt signaling leading to cell migration is largely unknown. We show, using genetically different or manipulated cultured cells, that Ror2 is critical for Wnt5a-induced, but not WNT3A-induced, cell migration. Ror2-mediated cell migration requires the extracellular cysteine-rich domain (CRD), which is the binding site for Wnt5a, and the cytoplasmic proline-rich domain (PRD) of Ror2. Furthermore, Ror2 can mediate filopodia formation via actin reorganization, irrespective of Wnt5a, and this Ror2-mediated filopodia formation requires the actin-binding protein filamin A, which associates with the PRD of Ror2. Intriguingly, disruption of filopodia formation by suppressing the expression of either Ror2 or filamin A inhibits Wnt5a-induced cell migration, indicating that Ror2-mediated filopodia formation is essential for Wnt5a-induced cell migration.
Yasuhiro Minami - One of the best experts on this subject based on the ideXlab platform.
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Genetic interactions between Ror2 and Wnt9a, Ror1 and Wnt9a and Ror2 and Ror1: Phenotypic analysis of the limb skeleton and palate in compound mutants.
Genes to cells : devoted to molecular & cellular mechanisms, 2019Co-Authors: Martina Weissenböck, Michiru Nishita, Yasuhiro Minami, Richard Latham, Lena Ingeborg Wolff, Christine HartmannAbstract:Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2-/- mutant mice. In contrast, Ror1-/- mutant mice are viable and show no limb phenotype. Ror1-/- ;Ror2-/- double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1hyp ) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a-/- single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2-/- mutants. Ror2-/- ;Wnt9a-/- double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1hyp/hyp ;Wnt9a-/- double mutants. In addition, Ror1hyp/hyp ;Wnt9a-/- double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.
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Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2
Genes to cells : devoted to molecular & cellular mechanisms, 2007Co-Authors: Hiroyuki Yamamoto, Michiru Nishita, Akira Kikuchi, Kan Yoo, Yasuhiro MinamiAbstract:The receptor tyrosine kinase Ror2 plays important roles in mediating non-canonical Wnt5a signaling by activating the Wnt–JNK pathway and inhibiting the β-catenin–TCF pathway. It has been shown that Ror2 is phosphorylated and activated by casein kinase Iɛ when both molecules are over-expressed in cultured cells. However, it remains unknown whether or not Ror2 is phosphorylated upon Wnt5a stimulation. Here we show that Ror2 is phosphorylated on serine/threonine residues upon stimulation of cultured cells, expressing Ror2 endogenously, with Wnt5a, but not WNT3A. It was found that treatment of cells with glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl and SB216763) or small interfering RNAs (siRNAs) for GSK-3 (mainly GSK-3α) can inhibit Wnt5a-induced phosphorylation of Ror2. Immunoprecipitated Ror2 can also be phosphorylated by purified GSK-3α or GSK-3βin vitro, and ectopic co-expression of Ror2 and GSK-3 (mainly GSK-3α) in cultured cells results in Ror2 phosphorylation, irrespective of Wnt5a, that is sensitive to SB216763. These results indicate that GSK-3 is involved in Wnt5a-induced phosphorylation of Ror2. Moreover, it was found that Wnt5a-induced cell migration can be inhibited by SB216763 or by siRNA-mediated suppression of GSK-3α (and GSK-3β) expression, further emphasizing the role(s) of GSK-3 in Wnt5a-induced signaling.
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filopodia formation mediated by receptor tyrosine kinase ror2 is required for wnt5a induced cell migration
Journal of Cell Biology, 2006Co-Authors: Michiru Nishita, Akira Nomachi, Yasutaka Ohta, Shinji Takada, Nagako Sougawa, Akira Kikuchi, Shuichi Kani, Yasuhiro MinamiAbstract:The receptor tyrosine kinase Ror2 plays important roles in developmental morphogenesis. It has recently been shown that Ror2 mediates Wnt5a-induced noncanonical Wnt signaling by activating the Wnt–JNK pathway and inhibiting the β-catenin–TCF pathway. However, the function of Ror2 in noncanonical Wnt signaling leading to cell migration is largely unknown. We show, using genetically different or manipulated cultured cells, that Ror2 is critical for Wnt5a-induced, but not WNT3A-induced, cell migration. Ror2-mediated cell migration requires the extracellular cysteine-rich domain (CRD), which is the binding site for Wnt5a, and the cytoplasmic proline-rich domain (PRD) of Ror2. Furthermore, Ror2 can mediate filopodia formation via actin reorganization, irrespective of Wnt5a, and this Ror2-mediated filopodia formation requires the actin-binding protein filamin A, which associates with the PRD of Ror2. Intriguingly, disruption of filopodia formation by suppressing the expression of either Ror2 or filamin A inhibits Wnt5a-induced cell migration, indicating that Ror2-mediated filopodia formation is essential for Wnt5a-induced cell migration.
Yue Yao - One of the best experts on this subject based on the ideXlab platform.
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HBO Promotes the Differentiation of Neural Stem Cells via Interactions Between the Wnt3/β-Catenin and BMP2 Signaling Pathways.
Cell transplantation, 2019Co-Authors: Chongfeng Chen, Yu-jia Yang, Yue YaoAbstract:Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of WNT3A, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of WNT3A, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.
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hbo promotes the differentiation of neural stem cells via interactions between the wnt3 β catenin and bmp2 signaling pathways
Cell Transplantation, 2019Co-Authors: Chongfeng Chen, Yu-jia Yang, Yue YaoAbstract:Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of WNT3A, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of WNT3A, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.
Shinji Takada - One of the best experts on this subject based on the ideXlab platform.
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deficiency of porcupine an o acyltransferase gene impairs convergent extension during gastrulation in zebrafish embryos and does not affect equivalently the trafficking of different wnt proteins
Journal of Cell Science, 2012Co-Authors: Qiuhong Chen, Ritsuko Takada, Shinji TakadaAbstract:Porcupine (Porcn), an O -acyltransferase located in the endoplasmic reticulum (ER), is required for lipidation of Wnt proteins in mammalian culture cells, and Porcn-mediated lipidation is required for trafficking of Wnt proteins from the ER. However, it is still unclear whether Porcn is equivalently required for trafficking of all members of the Wnt family. In this study, we investigated the function of Porcn in zebrafish embryos. We identified two zebrafish homologs of porcupine, porcn and porcupine-like (porcn-l) . Zebrafish porcn , but not porcn-l , restores secretion of Wnt proteins in porcn -deficient mouse L cells. Morpholino-mediated knockdown of porcn in zebrafish embryos impairs convergence and extension (CE) during gastrulation without changing embryonic patterning. Moreover, porcn interacts genetically with wnt5b and wnt11 in regulating CE. In contrast, porcn -deficient embryos do not exhibit phenotypes caused by failure in canonical Wnt signaling, which is activated by several Wnt ligands, including WNT3A. Furthermore, expression of genes regulated by the canonical Wnt signaling pathway is not perturbed in knockdown embryos relative to that in the controls. While the trafficking and lipidation of ectopically expressed zebrafish Wnt5b and mouse Wnt5a are impaired in porcn -deficient embryos, those of ectopically expressed WNT3A are less or no affected. In addition, the secretion of Wnt5a is inhibited by less amount of Porcn inhibitor than that of WNT3A in HEK293T cells. Thus, decrease of Porcn activity does not equivalently affect trafficking and lipidation of different Wnt proteins in zebrafish embryos and in mammalian culture cells.
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filopodia formation mediated by receptor tyrosine kinase ror2 is required for wnt5a induced cell migration
Journal of Cell Biology, 2006Co-Authors: Michiru Nishita, Akira Nomachi, Yasutaka Ohta, Shinji Takada, Nagako Sougawa, Akira Kikuchi, Shuichi Kani, Yasuhiro MinamiAbstract:The receptor tyrosine kinase Ror2 plays important roles in developmental morphogenesis. It has recently been shown that Ror2 mediates Wnt5a-induced noncanonical Wnt signaling by activating the Wnt–JNK pathway and inhibiting the β-catenin–TCF pathway. However, the function of Ror2 in noncanonical Wnt signaling leading to cell migration is largely unknown. We show, using genetically different or manipulated cultured cells, that Ror2 is critical for Wnt5a-induced, but not WNT3A-induced, cell migration. Ror2-mediated cell migration requires the extracellular cysteine-rich domain (CRD), which is the binding site for Wnt5a, and the cytoplasmic proline-rich domain (PRD) of Ror2. Furthermore, Ror2 can mediate filopodia formation via actin reorganization, irrespective of Wnt5a, and this Ror2-mediated filopodia formation requires the actin-binding protein filamin A, which associates with the PRD of Ror2. Intriguingly, disruption of filopodia formation by suppressing the expression of either Ror2 or filamin A inhibits Wnt5a-induced cell migration, indicating that Ror2-mediated filopodia formation is essential for Wnt5a-induced cell migration.
