Cadherin 6B induces BMP signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest

Park, Ki‐Sook; Gumbiner, Barry M.

doi:10.1242/dev.050096

Cited by 57 publications

(111 citation statements)

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“…Disruption or modulation of cadherin adhesions is an important step in initiating EMT (Clay and Halloran, 2011;Gumbiner, 2005;Nieto, 2011;Thiery et al, 2009;Wheelock et al, 2008). However, changes in cadherins are not always sufficient to induce EMT, indicating additional signals are required (Derksen et al, 2006;Knudsen et al, 2005;Maeda et al, 2005;Nelson et al, 2008;Park and Gumbiner, 2010). Here, we show that localized apical Rho-ROCK signaling in NCCs drives detachment of cell contacts, initiating motility within the neuroepithelium and EMT.…”

Section: Discussionmentioning

confidence: 71%

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Clay

Halloran

2013

Development

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Epithelial-to-mesenchymal transitions (EMTs) are crucial for morphogenesis and carcinoma metastasis, yet mechanisms controlling the underlying cell behaviors are poorly understood. RhoGTPase signaling has been implicated in EMT; however, previous studies have yielded conflicting results regarding Rho function, and its role in EMT remains poorly understood. Elucidation of precise Rho functions has been challenging because Rho signaling is highly context dependent and its activity is tightly regulated spatiotemporally within the cell. To date, few studies have examined how Rho affects cell motility in intact organisms, and the pattern of Rho activity during motile cell behaviors of EMT has not been determined in any system. Here, we image endogenous active Rho during EMT in vivo, and analyze effects of Rho and Rho-kinase (ROCK) manipulation on cell motility in vivo. We show that Rho is activated in a discrete apical region of premigratory neural crest cells during EMT, and Rho-ROCK signaling is essential for apical detachment and generation of motility within the neuroepithelium, a process that has been poorly understood. Furthermore, we find that Arhgap1 restricts Rho activation to apical areas, and this restriction is necessary for detachment. Our results provide new insight into mechanisms controlling local Rho activation and how it affects dynamic cell behaviors and actomyosin contraction during key steps of EMT in an intact living organism.

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Section: Discussionmentioning

confidence: 71%

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Clay

Halloran

2013

Development

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“…As only cranial neural crest cells express detectable Tspan18 (Fig. 1), and as Snail2 transcriptionally downregulates Cad6B prior to cranial but not trunk neural crest migration (Park and Gumbiner, 2010;Taneyhill et al, 2007), it appears that this coordinated transcriptional and postranslational regulation of Cad6B is a cranial-specific mechanism. Additional experiments are currently underway to further characterize the transcriptional regulation of Tspan18 by FoxD3.…”

Section: Tspan18 Post-translationally Maintains Cad6b Proteinmentioning

confidence: 97%

“…Another reason Tspan18 knockdown may not reliably elicit precocious migration is that loss of an epithelial cadherin is not the sole feature of EMT; to emigrate from the neural tube, the basal lamina must also break down, and neural crest cells must remodel their AJs to include cadherins that allow mesenchymal cell-cell adhesion during collective cell migration (Friedl and Wolf, 2003;Park and Gumbiner, 2010;Theveneau and Mayor, 2012). Although Cad6B protein is lost prematurely following Tspan18 knockdown, basal lamina break down and upregulation of the mesenchymal cadherin Cad7 still occur on the proper developmental timeline (Fig.…”

Section: Tspan18 Post-translationally Maintains Cad6b Proteinmentioning

confidence: 99%

“…At cranial levels, Cad6B downregulation is necessary for neural crest EMT, while E-cad expression persists in migratory cells Dady et al, 2012;Nakagawa and Takeichi, 1995;Nakagawa and Takeichi, 1998). On the other hand, trunk neural crest cells express Cad6B and N-cad but not E-cad, and N-cad is lost during EMT but Cad6B persists during migration (Dady et al, 2012;Nakagawa and Takeichi, 1995;Park and Gumbiner, 2010;Shoval et al, 2007). Subsequently, the less adhesive, type II cadherin-7 (Cad7) is upregulated in migratory neural crest cells all along the axis (Chu et al, 2006;Nakagawa and Takeichi, 1995;Nakagawa and Takeichi, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Tetraspanin18 is a FoxD3-responsive antagonist of cranial neural crest epithelial to mesenchymal transition that maintains Cadherin6B protein

Fairchild

Gammill

2013

Journal of Cell Science

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SummaryDuring epithelial-to-mesenchymal transition (EMT), tightly associated, polarized epithelial cells become individual mesenchymal cells capable of migrating. Here, we investigate the role of the transmembrane protein tetraspanin18 (Tspan18) in chick cranial neural crest EMT. Tspan18 mRNA is expressed in premigratory cranial neural crest cells, but is absent from actively migrating neural crest cells. Tspan18 knockdown leads to a concomitant loss of cadherin-6B (Cad6B) protein, whereas Cad6B protein persists when Tspan18 expression is extended. The temporal profile of Cad6B mRNA downregulation is unaffected in these embryos, which indicates that Tspan18 maintains Cad6B protein levels and reveals that Cad6B is regulated by post-translational mechanisms. Although downregulation of Tspan18 is necessary, it is not sufficient for neural crest migration: the timing of neural crest emigration, basal lamina breakdown and Cad7 upregulation proceed normally in Tspan18-deficient cells. This emphasizes the need for coordinated transcriptional and post-translational regulation of Cad6B during EMT and illustrates that Tspan18-antagonized remodeling of cell-cell adhesions is only one step in preparation for cranial neural crest migration. Unlike Cad6B, which is transcriptionally repressed by Snail2, Tspan18 expression is downstream of the winged-helix transcription factor FoxD3, providing a new transcriptional input into cranial neural crest EMT. Together, our data reveal post-translational regulation of Cad6B protein levels by Tspan18 that must be relieved by a FoxD3-dependent mechanism in order for cranial neural crest cells to migrate. These results offer new insight into the molecular mechanisms of cranial neural crest EMT and expand our understanding of tetraspanin function relevant to metastasis.

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“…Of interest, both noncanonical Wnt ligands and polarity proteins can regulate EMT and cell migration (Imai et al, 2006;Minichiello et al, 1999;Nishita et al, 2006;Witze et al, 2008), two processes that are characteristic for NC cell behavior. Since NC cells form at the boundary of neural and nonneural ectoderm, it is possible that the regulation of cadherinmediated cell adhesion contributes to the process of NC fate specification, in addition to its known function in NC migration (Kashef et al, 2009;Park and Gumbiner, 2010;Taneyhill, 2008). Of note, both Wnt11 signaling and the RhoV/Chp GTPase, which is required for NC formation, have been implicated in the maintenance of adherens junctions in zebrafish embryos (Tay et al, 2010;Ulrich et al, 2005).…”

Section: Research Articlementioning

confidence: 99%

Neural crest specification by noncanonical Wnt signaling and PAR-1

Ossipova

Sokol

2011

Development

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SUMMARYNeural crest (NC) cells are multipotent progenitors that form at the neural plate border, undergo epithelial-mesenchymal transition and migrate to diverse locations in vertebrate embryos to give rise to many cell types. Multiple signaling factors, including Wnt proteins, operate during early embryonic development to induce the NC cell fate. Whereas the requirement for the Wnt/b-catenin pathway in NC specification has been well established, a similar role for Wnt proteins that do not stabilize bcatenin has remained unclear. Our gain-and loss-of-function experiments implicate Wnt11-like proteins in NC specification in Xenopus embryos. In support of this conclusion, modulation of b-catenin-independent signaling through Dishevelled and Ror2 causes predictable changes in premigratory NC. Morpholino-mediated depletion experiments suggest that Wnt11R, a Wnt protein that is expressed in neuroectoderm adjacent to the NC territory, is required for NC formation. Wnt11-like signals might specify NC by altering the localization and activity of the serine/threonine polarity kinase PAR-1 (also known as microtubule-associated regulatory kinase or MARK), which itself plays an essential role in NC formation. Consistent with this model, PAR-1 RNA rescues NC markers in embryos in which noncanonical Wnt signaling has been blocked. These experiments identify novel roles for Wnt11R and PAR-1 in NC specification and reveal an unexpected connection between morphogenesis and cell fate.

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Cadherin 6B induces BMP signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest

Cited by 57 publications

References 51 publications

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition

Tetraspanin18 is a FoxD3-responsive antagonist of cranial neural crest epithelial to mesenchymal transition that maintains Cadherin6B protein

Neural crest specification by noncanonical Wnt signaling and PAR-1

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