Human neural crest induction by temporal modulation of WNT activation

Gomez, Gustavo A.; Prasad, Maneeshi S.; Sandhu, Nabjot; Shelar, Patrick B.; Leung, Alan W.; Garcı́a-Castro, Martı́n I.

doi:10.1016/j.ydbio.2019.02.015

Cited by 43 publications

(52 citation statements)

References 28 publications

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“…S1C). The percentage of nuclei positively stained for PAX7 and SOX10 at low WNT is close to 60% (Gomez et al, 2019;Leung et al, 2016); instead, high-WNT cultures display >75% doublepositive cells (Fig. 1C).…”

Section: Introductionmentioning

confidence: 95%

“…We have previously reported that low-WNT anterior NCCs generate melanoblasts, peripheral neurons, glia and ectomesenchymal derivatives according to their axial identity (Gomez et al, 2019;Leung et al, 2016). We therefore evaluated the differentiation potential of posterior NCCs induced with high WNT.…”

Section: High-wnt Nccs Display Posterior Differentiation Potential Anmentioning

confidence: 99%

“…We have previously reported an effective model of human NC formation that generates anterior NCCs from pluripotent stem cells through activation of the WNT/β-catenin pathway either for 5 days (Leung et al, 2016) or just the first 2 days of the 5-day culture (Gomez et al, 2019). To further explore the effect of the magnitude of the WNT signal, we first assessed the effect of different concentrations of CHIR99021 (CHIR), a potent and wellcharacterized WNT inducer (Ring et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

et al. 2019

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WNT/β-catenin signaling is crucial for neural crest (NC) formation, yet the effects of the magnitude of the WNT signal remain ill-defined. Using a robust model of human NC formation based on human pluripotent stem cells (hPSCs), we expose that the WNT signal modulates the axial identity of NCs in a dose-dependent manner, with low WNT leading to anterior OTX + HOX − NC and high WNT leading to posterior OTX − HOX + NC. Differentiation tests of posterior NC confirm expected derivatives, including posterior-specific adrenal derivatives, and display partial capacity to generate anterior ectomesenchymal derivatives. Furthermore, unlike anterior NC, posterior NC exhibits a transient TBXT + /SOX2 + neuromesodermal precursor-like intermediate. Finally, we analyze the contributions of other signaling pathways in posterior NC formation, which suggest a crucial role for FGF in survival/proliferation, and a requirement of BMP for NC maturation. As expected retinoic acid (RA) and FGF are able to modulate HOX expression in the posterior NC. Surprisingly, early RA supplementation prohibits NC formation. This work reveals for the first time that the amplitude of WNT signaling can modulate the axial identity of NC cells in humans.

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Section: Introductionmentioning

confidence: 95%

Section: High-wnt Nccs Display Posterior Differentiation Potential Anmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

et al. 2019

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“…These data suggest that DDX3-regulated AKT-GSK3b signaling axis induces NC through Snai1 in addition to bcatenin. Currently, most protocols for inducing the NC from human pluripotent stem cells include GSK3b inhibition, which is thought to activate canonical Wnt signaling through b-catenin stabilization (Gomez et al, 2019;Leung et al, 2016;Menendez et al, 2011;Mica et al, 2013). In light of our results, it would be of interest to examine if the stabilization of Snai1 also contributes to the NC induction abilities of GSK3b inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…A major signaling pathway that induces the NC in non-mammalian vertebrates is canonical Wnt/b-catenin signaling (hereinafter referred to as "Wnt signaling"), which is required for both the initial formation of the NPB and the subsequent specification of the NC (Li et al, 2018;Prasad et al, 2019). Similarly, the induction of NC from human embryonic stem (ES) cells or induced pluripotent stem (iPS) cells also requires the activation of Wnt signaling (Gomez et al, 2019;Leung et al, 2016;Menendez et al, 2011;Mica et al, 2013), indicating that Wnt function in NC induction is conserved during vertebrate evolution.…”

Section: Introductionmentioning

confidence: 99%

The RNA helicase DDX3 induces neural crest by promoting AKT activity

Perfetto

Yousaf

et al. 2019

Preprint

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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.

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Symmetry Breaking of Human Pluripotent Stem Cells (hPSCs) in Micropattern Generates a Polarized Spinal Cord‐Like Organoid (pSCO) with Dorsoventral Organization

et al. 2023

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Axis formation and related spatial patterning are initiated by symmetry breaking during development. A geometrically confined culture of human pluripotent stem cells (hPSCs) mimics symmetry breaking and cell patterning. Using this, polarized spinal cord organoids (pSCOs) with a self-organized dorsoventral (DV) organization are generated. The application of caudalization signals promoted regionalized cell differentiation along the radial axis and protrusion morphogenesis in confined hPSC colonies. These detached colonies grew into extended spinal cord-like organoids, which established self-ordered DV patterning along the long axis through the spontaneous expression of polarized DV patterning morphogens. The proportions of dorsal/ventral domains in the pSCOs can be controlled by the changes in the initial size of micropatterns, which altered the ratio of center-edge cells in 2D. In mature pSCOs, highly synchronized neural activity is separately detected in the dorsal and ventral side, indicating functional as well as structural patterning established in the organoids. This study provides a simple and precisely controllable method to generate spatially ordered organoids for the understanding of the biological principles of cell patterning and axis formation during neural development.

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Human neural crest induction by temporal modulation of WNT activation

Cited by 43 publications

References 28 publications

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

The RNA helicase DDX3 induces neural crest by promoting AKT activity

Symmetry Breaking of Human Pluripotent Stem Cells (hPSCs) in Micropattern Generates a Polarized Spinal Cord‐Like Organoid (pSCO) with Dorsoventral Organization

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