scholarly journals PFKFB4 control of Akt signaling is essential for premigratory and migratory neural crest formation

2017 ◽  
Author(s):  
Ana Leonor Figueiredo ◽  
Frédérique Maczkowiak ◽  
Caroline Borday ◽  
Patrick Pla ◽  
Meghane Sittewelle ◽  
...  
Keyword(s):  
Neural Crest ◽  
Early Phase ◽  
Akt Signaling ◽  
Neural Plate ◽  
Summary Statement ◽  
And Migration ◽  
Craniofacial Defects ◽  
Later Phase ◽  
Adult Cells

Summary statementPFKFB4 controls neural crest final specification and migration by regulation of AKT signaling or glycolysis.AbstractNeural crest (NC) specification comprises an early phase, initiating immature NC progenitors formation at neural plate stage, and a later phase at neural fold stage, resulting into functional premigratory NC, able to delaminate and migrate. We found that the NC-GRN triggers up-regulation of pfkfb4 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4) during this late specification phase. As shown in previous studies, PFKFB4 controls AKT signaling in gastrulas and glycolysis rate in adult cells. Here, we focus on PFKFB4 function in NC during and after neurulation, using time-controlled or hypomorph depletions in vivo. We find that PFKFB4 is essential both for specification of functional premigratory NC and for its migration. PFKFB4-depleted embryos fail activating n-cadherin and late NC specifiers, exhibit severe migration defects, resulting in craniofacial defects. AKT signaling mediates PFKFB4 function in NC late specification, while both AKT signaling and glycolysis regulate migration. These findings highlight novel and critical roles of PFKFB4 activity in later stages of NC development, wired into the NC-GRN.

scholarly journals Cadherin-6B proteolysis promotes the neural crest cell epithelial-to-mesenchymal transition through transcriptional regulation

2016 ◽  
Vol 215 (5) ◽  
pp. 735-747 ◽  
Author(s):  
Andrew T. Schiffmacher ◽  
Vivien Xie ◽  
Lisa A. Taneyhill
Keyword(s):  
Neural Crest ◽  
Epithelial To Mesenchymal Transition ◽  
Neural Crest Cell ◽  
Cranial Neural Crest ◽  
Mesenchymal Transition ◽  
Effector Genes ◽  
A Disintegrin And Metalloproteinase ◽  
And Migration ◽  
Cranial Neural Crest Cells

During epithelial-to-mesenchymal transitions (EMTs), cells disassemble cadherin-based junctions to segregate from the epithelia. Chick premigratory cranial neural crest cells reduce Cadherin-6B (Cad6B) levels through several mechanisms, including proteolysis, to permit their EMT and migration. Serial processing of Cad6B by a disintegrin and metalloproteinase (ADAM) proteins and γ-secretase generates intracellular C-terminal fragments (CTF2s) that could acquire additional functions. Here we report that Cad6B CTF2 possesses a novel pro-EMT role by up-regulating EMT effector genes in vivo. After proteolysis, CTF2 remains associated with β-catenin, which stabilizes and redistributes both proteins to the cytosol and nucleus, leading to up-regulation of β-catenin, CyclinD1, Snail2, and Snail2 promoter-based GFP expression in vivo. A CTF2 β-catenin–binding mutant, however, fails to alter gene expression, indicating that CTF2 modulates β-catenin–responsive EMT effector genes. Notably, CTF2 association with the endogenous Snail2 promoter in the neural crest is β-catenin dependent. Collectively, our data reveal how Cad6B proteolysis orchestrates multiple pro-EMT regulatory inputs, including CTF2-mediated up-regulation of the Cad6B repressor Snail2, to ensure proper cranial neural crest EMT.

scholarly journals From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo

2017 ◽  
Author(s):  
Daria Gavriouchkina ◽  
Ruth M Williams ◽  
Martyna Lukoseviciute ◽  
Tatiana Hochgreb-Hägele ◽  
Upeka Senanayake ◽  
...  
Keyword(s):  
Neural Crest ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Stem Cell Population ◽  
Cell Fates ◽  
Developmental Potential ◽  
Regulatory Circuits ◽  
And Migration ◽  
Gene Regulatory Circuits

AbstractThe neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant versus wild type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffing nucleosomes. Strikingly, foxd3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from permissive to repressive nucleosome/chromatin organisation to maintain stemness and define cell fates.

scholarly journals AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 751
Author(s):  
Camille Laberthonnière ◽  
Elva Maria Novoa-del-Toro ◽  
Raphaël Chevalier ◽  
Natacha Broucqsault ◽  
Vanitha Venkoba Rao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Neural Crest ◽  
Differential Expression ◽  
Biological Networks ◽  
Neural Crest Cells ◽  
Akt Signaling ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
And Migration

Over the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation–migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS.

scholarly journals Neural crest induction in Xenopus: evidence for a two-signal model

Development ◽  
1998 ◽  
Vol 125 (13) ◽  
pp. 2403-2414 ◽  
Author(s):  
C. LaBonne ◽  
M. Bronner-Fraser
Keyword(s):  
Neural Crest ◽  
Neural Tissue ◽  
Neural Plate ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Signal Model ◽  
Zinc Finger Transcription Factor ◽  
Step Model ◽  
Wnt Signal

We have investigated the molecular interactions underlying neural crest formation in Xenopus. Using chordin overexpression to antagonize endogenous BMP signaling in whole embryos and explants, we demonstrate that such inhibition alone is insufficient to account for neural crest induction in vivo. We find, however, that chordin-induced neural plate tissue can be induced to adopt neural crest fates by members of the FGF and Wnt families, growth factors that have previously been shown to posteriorize induced neural tissue. Overexpression of a dominant negative XWnt-8 inhibits the expression of neural crest markers, demonstrating the necessity for a Wnt signal during neural crest induction in vivo. The requirement for Wnt signaling during neural crest induction is shown to be direct, whereas FGF-mediated neural crest induction may be mediated by Wnt signals. Overexpression of the zinc finger transcription factor Slug, one of the earliest markers of neural crest formation, is insufficient for neural crest induction. Slug-expressing ectoderm will generate neural crest in the presence of Wnt or FGF-like signals, however, bypassing the need for BMP inhibition in this process. A two-step model for neural crest induction is proposed.

scholarly journals IGF2BP2 Promotes the Proliferation, Invasion and Migration of Esophageal Carcinoma Cells via Activation of the PI3K/AKT/EMT Signaling Pathway

2021 ◽  
Author(s):  
Wenbin Shu ◽  
YuJing Lin ◽  
Yan Yan ◽  
YaoHui Sun ◽  
XiangWen Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
And Migration ◽  
Mrna Binding

Abstract BackgroundInsulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2), as a m6A “reader”, is known to be an oncogene, and its expression is elevated in multiple tumors. However, the role of IGF2PB2 in esophageal squamous cell carcinoma (ESCC) is still unclear. MethodsThis study aims to investigate the role of IGF2PB2 expression in ESCC proliferation, invasion and migration as well as the possible mechanism. IGF2BP2 expression was found to be elevated in ESCC tissues by qRT-PCR, western blotting, and immunohistochemical (IHC) staining. ResultsKnocking down IGF2BP2 expression prevented the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of KYSE450 and TE1 cells. Knocking out IGF2BP2 reduced tumorigenesis in vivo. Overexpression of IGF2BP2 was performed, and it was proven that IGF2BP2 had an oncogenic effect in KYSE450 and TE1 cells. Moreover, LY294002, a highly selective inhibitor of PI3K, reversed the effect of IGF2BP2 overexpression on EMT processes. All these results show that the effects of IGF2BP2 on oncogenesis and EMT were clearly exerted via the PI3K/AKT signaling pathway. ConclusionsIn conclusion, this study demonstrates that the oncogenic function of IGF2BP2 is mediated by the PI3K/AKT signaling pathway and is related to EMT in ESCC. In addition, IGF2BP2 can serve as a diagnostic and oncotherapeutic marker in further studies.

scholarly journals Overexpression of long non-coding RNA LINC00982 suppresses cell proliferation and tumor growth of papillary thyroid carcinoma through PI3K-ATK signaling pathway

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Debin Xu ◽  
Jichun Yu ◽  
Shimin Zhuang ◽  
Shuyong Zhang ◽  
Zhengdong Hong ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Expression Levels ◽  
And Migration ◽  
Proliferation And Migration

Abstract Long non-coding RNAs (lncRNAs) have been widely reported that involved in human cancers, including papillary thyroid carcinoma (PTC). The present study aims to investigate the biological role of LINC00982 in PTC. The mRNA expression of LINC00982 in human PTC tissues was detected using qPCR. Moreover, Kaplan–Meier method was performed to analyze the internal relevance between LINC00982 expression and overall survival (OS) rate of patients with PTC. In addition, gain- and loss-of-functions assays were performed to detect the effects of LINC00982 on the cell proliferation and migration in PTC cells. Furthermore, western blot assay was used to measure the alteration expression levels of apoptosis relative proteins and the relative protein involved phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Finally, a xenograft model was used to analyze the antitumor role of LINC00982 in vivo. Here, we found that LINC00982 was decreased in human PTC tissues. Patients with decreased LINC00982 expression levels had a reduced OS (P=0.0019) compared with those with high LINC00982 expression levels. Overexpression of LINC00982 suppressed the proliferation and migration of BHT101 and B-CPAP cells and promoted cell apoptosis. Knockdown of LINC00982 promoted the proliferation and migration of BHT101 and B-CPAP cells and induced cell apoptosis. Moreover, in vivo assay showed that overexpression of LINC00982 could suppress the growth of PTC. Finally, LINC00982 could regulate the activity of PI3K/AKT signaling pathway in vitro and in vivo. Taken together, our findings demonstrated that overexpression of LINC00982 could suppress cell proliferation and induce cell apoptosis by regulating PI3K/AKT signaling pathway in PTC.

scholarly journals Down-regulated microRNA-30b-3p inhibits proliferation, invasion and migration of glioma cells via inactivation of the AKT signaling pathway by up-regulating RECK

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Yan Jian ◽  
Chun-Hua Xu ◽  
You-Ping Li ◽  
Bin Tang ◽  
She-Hao Xie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glioma Cells ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Related Factors ◽  
Invasion And Migration ◽  
And Migration

AbstractmicroRNAs (miRNAs) have been found to affect various cancers, and expression of numerous miRNAs is revealed in glioma. However, the role of microRNA-30b-3p (miR-30b-3p) in glioma remains elusive. Therefore, the present study aims to explore the specific mechanism by which miR-30b-3p influence the development of glioma in relation to the AKT signaling pathway. First, glioma cell lines were collected with miR-30b-3p and reversion-inducing cysteine-rich protein with kazal motifs (RECK) expression measured. The functional role of miR-30b-3p and RECK in glioma was determined via gain- and loss-of-function approaches. Subsequently, the expression of invasion- and migration-related factors (MMP-2 and MMP-9) and the AKT signaling pathway-related factors (AKT, p-AKT and PI3K-p85) was detected. Moreover, in vivo experiments were also conducted to investigate how miR-30b-3p influences in vivo tumorigenesis. The results showed that miR-30b-3p was up-regulated and RECK was down-regulated in glioma. RECK was a target gene of miR-30b-3p. Decreased miR-30b-3p and overexpressed RECK led to decreased expression of MMP-2, MMP-9 and p-AKT. Overexpressed RECK and LY294002 could decrease p-AKT and PI3K-p85 expression accompanied with unchanged expression of total protein of AKT. Additionally, proliferation, migration and invasion of glioma cells and tumor formation in nude mice were repressed owing to reduced expression of miR-30b-3p or elevated expression of RECK. In summary, miR-30b-3p inhibition suppresses metastasis of glioma cells by inactivating the AKT signaling pathway via RECK up-regulation, providing a new target for glioma treatment.

scholarly journals Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5818
Author(s):  
Alessandra Pagano ◽  
Gilles Breuzard ◽  
Fabrice Parat ◽  
Aurélie Tchoghandjian ◽  
Dominique Figarella-Branger ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Xenograft Model ◽  
Akt Signaling ◽  
Low Grade ◽  
Multicellular Spheroids ◽  
Phosphorylated Akt ◽  
Cell Organization ◽  
Tcga Dataset ◽  
And Migration

The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of MAPT RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.

The transcription factor Sox9 is required for cranial neural crest development inXenopus

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 421-432 ◽  
Author(s):  
Rebecca F. Spokony ◽  
Yoichiro Aoki ◽  
Natasha Saint-Germain ◽  
Emily Magner-Fink ◽  
Jean-Pierre Saint-Jeannet
Keyword(s):  
Neural Crest ◽  
Cell Fate ◽  
Neural Plate ◽  
Cranial Neural Crest ◽  
Pharyngeal Arches ◽  
Skeletal Malformations ◽  
Xy Sex Reversal ◽  
Human Disorder ◽  
Antisense Oligos ◽  
Craniofacial Defects

The SOX family of transcription factors has been implicated in cell fate specification during embryogenesis. One member of this family, Sox9, has been shown to regulate both chondrogenesis and sex determination in the mouse embryo. Heterozygous mutations in Sox9 result in Campomelic Dysplasia (CD), a lethal human disorder characterized by autosomal XY sex reversal, severe skeletal malformations and several craniofacial defects. Sox9 is also expressed in neural crest progenitors but very little is known about the function of Sox9 in the neural crest. We have cloned the Xenopus homolog of the Sox9 gene. It is expressed maternally and accumulates shortly after gastrulation at the lateral edges of the neural plate, in the neural crest-forming region. As development proceeds, Sox9 expression persists in migrating cranial crest cells as they populate the pharyngeal arches. Depletion of Sox9 protein in developing embryos, using morpholino antisense oligos, causes a dramatic loss of neural crest progenitors and an expansion of the neural plate. Later during embryogenesis, morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements, mimicking one aspect of the craniofacial defects observed in CD patients. We propose that Sox9 is an essential component of the regulatory pathway that leads to cranial neural crest formation.

scholarly journals The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development

2020 ◽  
Author(s):  
Martha L. Echevarría-Andino ◽  
Benjamin L. Allen
Keyword(s):  
Neural Crest ◽  
Hedgehog Signaling ◽  
Developmental Time ◽  
Craniofacial Development ◽  
Pathway Activity ◽  
Tissue Specific ◽  
Summary Statement ◽  
Hh Signaling ◽  
The Individual ◽  
Craniofacial Defects

AbstractThe Hedgehog (HH) pathway controls multiple aspects of craniofacial development. HH ligands signal through the canonical receptor PTCH1, and three co-receptors– GAS1, CDON and BOC. Together, these co-receptors are required during embryogenesis to mediate proper HH signaling. Here we investigated the individual and combined contributions of GAS1, CDON and BOC to HH-dependent mammalian craniofacial development. Individual deletion of either Gas1 or Cdon results in variable holoprosencephaly phenotypes, characterized by the failure to divide and form the telencephalon and midfacial structures. In contrast, we find that Boc deletion results in facial widening consistent with increased HH pathway activity. Additionally, the deletion of Boc in a Gas1 null background partially rescues the craniofacial defects observed in Gas1 single mutants; a phenotype that persists over developmental time. This contrasts with HH-dependent phenotypes in other tissues that significantly worsen following combined deletion of Gas1 and Boc. Mechanistically, BOC selectively restricts neural crest-derived mesenchymal proliferation. Together, these data indicate that BOC acts as a multi-functional regulator of HH signaling during craniofacial development, alternately promoting or restraining HH pathway activity in a tissue-specific fashion.Summary statementHere we identify dual, tissue-specific roles for the Hedgehog co-receptor BOC in both the promotion and antagonism of Hedgehog signaling during craniofacial development.

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