The Nodal Precursor Acting via Activin Receptors Induces Mesoderm by Maintaining a Source of Its Convertases and BMP4

Ben-Haim, Nadav; Lu, Cindy C.; Guzman-Ayala, Marcela; Pescatore, L.; Mesnard, Daniel; Bischofberger, Mirko; Naef, Félix; Robertson, Elizabeth J.; Constam, Daniel

doi:10.1016/j.devcel.2006.07.005

Cited by 290 publications

(313 citation statements)

References 45 publications

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“…In one example, Eimon and Harland (2002) demonstrated that overexpressed cleavage-resistant Xnr2 was capable of inducing the expression of mesodermal genes in Xenopus embryos, although this activity was weaker than normal protein, and has so far not been detected by other groups (Osada and Wright, 1999;Onuma et al, 2002Onuma et al, , 2005HashimotoPartyka et al, 2003); the reason for this discrepancy remains unclear. A similar activity was reported for a non-cleavable form of mouse Nodal, and the proprotein has been suggested to be able to bind and signal through Activin receptors to induce significant expression of BMP4, furin/ spc1, and spc4 (Ben-Haim et al, 2006). Yet another report demonstrated that the proprotein of human Lefty A could activate the MAP kinase pathway in P19 mouse embryonic carcinoma cells (Ulloa et al, 2001).…”

Section: Introductionsupporting

confidence: 64%

“…SPCs may, therefore, work in both a cellautonomous and non-cell-autonomous manner (Nakayama, 1997;Molloy et al, 1999). SPC-mediated cleavage releases the active ligand during the maturation of TGF␤ proteins (Kingsley, 1994;Nakayama, 1997;Cui et al, 1998;Constam and Robertson, 1999;Molloy et al, 1999;Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002;Ben-Haim et al, 2006). Although mammalian Lefty molecules have been shown to undergo proteolytic cleavage by SPC1, SPC4, and SPC6 in several transfected cell lines, the endogenous SPC enzyme(s) that is involved in proteolytic processing of Lefty in vivo is currently not known (Ulloa et al, 2001;Beck et al, 2002;Sakuma et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Westmoreland

Takahashi

Wright

2007

Developmental Dynamics

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The Nodal and Nodal-related morphogens are utilized for the specification of distinct cellular identity throughout development by activating discrete target genes in a concentration-dependant manner. Lefty is a principal extracellular antagonist involved in the spatiotemporal regulation of the Nodal morphogen gradient during mesendoderm induction. The Xenopus Lefty proprotein contains a single N-linked glycosylation motif in the mature domain and two potential cleavage sites that would be expected to produce long (Xlefty L ) and short (Xlefty S ) isoforms. Here we demonstrate that both isoforms were secreted from Xenopus oocytes, but that Xlefty L is the only isoform detected when embryonic tissue was analyzed. In mesoderm induction assays, Xlefty L is the functional blocker of Xnr signaling. When secreted from oocytes, vertebrate Lefty molecules were N-linked glycosylated. However, glycan addition was not required to inhibit Xnr signaling and did not influence its movement through the extracellular space. These findings demonstrate that Lefty molecules undergo post-translational modifications and that some of these modifications are required for the Nodal inhibitory function.

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Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Westmoreland

Takahashi

Wright

2007

Developmental Dynamics

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“…27 In certain contexts, Nodal-ALK4 signaling might also proceed in the absence of Cripto. 30,31 In addition, Nodal may block bone morphogenetic protein (BMP) signaling by direct dimerization with the BMP ligand in a Cripto-independent manner. 29 Nodal signaling in melanomas may be Cripto independent, because only a small sub-population of cultured C8161 melanoma cells express Cripto.…”

Section: Discussionmentioning

confidence: 99%

Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions

Harms

Pouryazdanparast

et al. 2010

Modern Pathology

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Nodal, a potent embryonic morphogen in the transforming growth factor-b family, is a proposed key regulator of melanoma tumorigenicity. However, there has been no systematic study of Nodal expression in melanocytic lesions. We investigated Nodal expression by immunohistochemistry in 269 melanocytic lesions, including compound nevi, dysplastic nevi, congenital nevi, Spitz nevi, melanoma in situ, malignant melanoma including the variant desmoplastic melanoma, and metastatic melanoma. We found that the Nodal expression was significantly increased in malignant lesions (including melanoma in situ, malignant melanoma, and metastatic melanoma) compared with compound nevi, Spitz nevi, and dysplastic nevi. Surprisingly, congenital nevi expressed a level of Nodal comparable with malignant lesions, whereas desmoplastic melanoma showed lower expression than nondesmoplastic malignant melanoma (Po0.05). Deep melanoma (Breslow depth 41 mm) displayed a higher percentage of Nodal-positive tumor cells than did superficial melanoma (Breslow depth r1 mm), although there was no statistical difference in the overall staining intensity (P ¼ 0.18). Melanomas in situ showed a lower level of Nodal expression than did deep melanomas and metastatic melanomas (Po0.05). The low expression of Nodal in normal and dysplastic nevi, and its increasing expression with the progression of malignant lesions, are suggestive of a role for Nodal in melanoma progression.

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“…6E-F′). The extra-embryonic ectoderm-derived BMP4, involved in Cripto and Wnt3 induction (Beck et al, 2002;Ben-Haim et al, 2006), was also expressed in E6.5 N1ICD epi embryos (data not shown). Moreover, the WNT3/β-catenin pathway was active in N1ICD epi embryos, as shown by the expression of its targets Axin2 and Sp5 (n=5 and n=6, respectively; Fig.…”

Section: Notch Activation Impairs Axial Mesoderm Formation and Perturmentioning

confidence: 92%

“…S2). The maintenance of Nodal expression in the epiblast, the primitive streak and the VE depends both on an autoregulatory loop involving NODAL signalling through its co-receptor CRIPTO (TDGF1), on the transcription factor OCT4, and on the WNT3/β-catenin pathway (Adachi et al, 1999;Ben-Haim et al, 2006;Granier et al, 2011; 2002; Norris and Robertson, 1999;Papanayotou et al, 2014). Oct4, Cripto and Wnt3 were all normally expressed in E6.5 N1ICD epi embryos (n=3, n=5 and n=3, respectively; Fig.…”

Section: Notch Activation Impairs Axial Mesoderm Formation and Perturmentioning

confidence: 99%

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

et al. 2015

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NOTCH signalling is an evolutionarily conserved pathway involved in intercellular communication essential for cell fate choices during development. Although dispensable for early aspects of mouse development, canonical RBPJ-dependent NOTCH signalling has been shown to influence lineage commitment during embryonic stem cell (ESC) differentiation. NOTCH activation in ESCs promotes the acquisition of a neural fate, whereas its suppression favours their differentiation into cardiomyocytes. This suggests that NOTCH signalling is implicated in the acquisition of distinct embryonic fates at early stages of mammalian development. In order to investigate in vivo such a role for NOTCH signalling in shaping cell fate specification, we use genetic approaches to constitutively activate the NOTCH pathway in the mouse embryo. Early embryonic development, including the establishment of anterior-posterior polarity, is not perturbed by forced NOTCH activation. By contrast, widespread NOTCH activity in the epiblast triggers dramatic gastrulation defects. These are fully rescued in a RBPJ-deficient background. Epiblast-specific NOTCH activation induces acquisition of neurectoderm identity and disrupts the formation of specific mesodermal precursors including the derivatives of the anterior primitive streak, the mouse organiser. In addition, we show that forced NOTCH activation results in misregulation of NODAL signalling, a major determinant of early embryonic patterning. Our study reveals a previously unidentified role for canonical NOTCH signalling during mammalian gastrulation. It also exemplifies how in vivo studies can shed light on the mechanisms underlying cell fate specification during in vitro directed differentiation.

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The Nodal Precursor Acting via Activin Receptors Induces Mesoderm by Maintaining a Source of Its Convertases and BMP4

Cited by 290 publications

References 45 publications

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Xenopus Lefty requires proprotein cleavage but not N‐linked glycosylation to inhibit nodal signaling

Expression of the embryonic morphogen Nodal in cutaneous melanocytic lesions

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

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