PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis

Pegoraro, Caterina; Figueiredo, Ana Leonor; Maczkowiak, Frédérique; Pouponnot, Célio; Eychène, Alain; Monsoro-Burq, Anne H.

doi:10.1038/ncomms6953

Cited by 36 publications

(59 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Possible non-glycolytic functions for PFKP must therefore also be considered. It is potentially noteworthy that a non-glycolytic role in early dorsal patterning has recently been demonstrated for PFKFB4, one of five known isoforms of phosphofructokinase-2 (PFK-2) [67].…”

Section: (B) Copy Number Variant Analyses Identify Novel Heterotaxy Gmentioning

confidence: 99%

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

Cowan

Tariq

Shaw

et al. 2016

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

Genomic disorders and rare copy number abnormalities are identified in 15–25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left–right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 ( PFKP ) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

show abstract

Section: (B) Copy Number Variant Analyses Identify Novel Heterotaxy Gmentioning

confidence: 99%

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

Cowan

Tariq

Shaw

et al. 2016

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

show abstract

“…Furthermore, WB showed that neither NES nor Sox10 was expressed when PI3K/Akt or MAPK/Erk1/2 pathway was blocked. The effect of Akt pathway in pluripotency has been recently discussed in the context of embryonic and progenitor cell differentiation patterns . Furthermore, activating MEK was shown to prolong the expression of pluripotency marker Sox3, a Sox family member that is also regulated by FGF signaling .…”

Section: Discussionmentioning

confidence: 99%

“…The effect of Akt pathway in pluripotency has been recently discussed in the context of embryonic and progenitor cell differentiation patterns. 29 Furthermore, activating MEK was shown to prolong the expression of pluripotency marker Sox3, 28 a Sox family member that is also regulated by FGF signaling. 30 On the other hand, inhibition of Rac had no effect on the number of NES+ cells after 8 days of induction.…”

Section: Discussionmentioning

confidence: 99%

Derivation of neural crest stem cells from human epidermal keratinocytes requires FGF‐2, IGF‐1, and inhibition of TGF‐β1

Tseropoulos

Boroujeni

Bajpai

et al. 2018

Bioengineering & Transla Med

View full text Add to dashboard Cite

Neural crest (NC) cells play a central role in forming the peripheral nervous system, the craniofacial skeleton, and the pigmentation of the skin during development due to their broad multilineage differentiation potential into neurons, Schwann cells, melanocytes, and mesenchymal stem cells. Recently, we identified an easily accessible source of pluripotent NC stem cells from human inter‐follicular keratinocyte (KC) cultures (KC‐NC). In this work, we examined specific conditions for the derivation of NC from KC cultures. More specifically, we examined the role of two growth factors, FGF2 and IGF1, in NC proliferation and in expression of two potent NC transcription factors, Sox10 and FoxD3. Using specific chemical inhibitors, we uncovered that the downstream regulatory pathways AKT/PI3K, MEK/ERK, and JNK/cJun may be critical in Sox10 and FoxD3 regulation in KC‐NC. The TGF‐β1 pathway was also implicated in suppressing Sox10 expression and NC proliferation. In summary, our study shed light into the role of FGF2, IGF1, and TGF‐β1 on the induction of NC from KC cultures and the pathways that regulate Sox10 and FoxD3. We also established culture conditions for sustaining KC‐NC multipotency and, therefore, the potential of these cells for regenerative medicine and cellular therapies.

show abstract

“…1). In addition, phosphatidylinositol 3-kinase (PI3K), a kinase that activates AKT, regulates NC induction in Xenopus laevis, a species closely related to X. tropicalis, although the exact roles of PI3K in NC induction remain controversial (Geary and LaBonne, 2018;Pegoraro et al, 2015). We therefore asked if DDX3 KD interferes with the AKT-GSK3b signaling axis.…”

Section: Depletion Of Ddx3 Leads To Reduced Akt Activity and Akt-depementioning

confidence: 99%

“…The function of PI3K-AKT signaling in NC induction is controversial. While treatment of gastrula-stage X. laevis embryos with a PI3K inhibitor reduces the expression of NC markers, a constitutively active form of PI3K can also reduce NC markers induced by Pax3 and Zic1 in isolated X. laevis animal caps, which are thought to contain pluripotent stem cells (Buitrago-Delgado et al, 2015;Geary and LaBonne, 2018;Pegoraro et al, 2015). However, PI3K has AKT-independent function (Faes and Dormond, 2015), and the mechanisms underlying the possible roles of AKT in NC induction remains largely unknown.…”

Section: Akt Is a Key Regulator Of Wnt/b-catenin Signaling And Nc Indmentioning

confidence: 99%

The RNA helicase DDX3 induces neural crest by promoting AKT activity

Perfetto

Yousaf

et al. 2019

Preprint

View full text Add to dashboard Cite

Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many patients carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3b, leading to reduced levels of b-catenin and Snai1, two GSK3b substrates that are critical for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by patients harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

show abstract

PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis

Cited by 36 publications

References 56 publications

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

Derivation of neural crest stem cells from human epidermal keratinocytes requires FGF‐2, IGF‐1, and inhibition of TGF‐β1

The RNA helicase DDX3 induces neural crest by promoting AKT activity

Contact Info

Product

Resources

About