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.

Anterior mesendoderm induces mouse Engrailed genes in explant cultures

Development ◽  
1993 ◽  
Vol 118 (1) ◽  
pp. 139-149 ◽  
Author(s):  
S.L. Ang ◽  
J. Rossant
Keyword(s):  
Direct Evidence ◽  
Neural Tissue ◽  
Explant Culture ◽  
Neural Plate ◽  
Explant Cultures ◽  
Neural Marker ◽  
Engrailed Genes ◽  
Anterior Posterior

We have developed germ layer explant culture assays to study the role of mesoderm in anterior-posterior (A-P) patterning of the mouse neural plate. Using isolated explants of ectodermal tissue alone, we have demonstrated that the expression of Engrailed-1 (En-1) and En-2 genes in ectoderm is independent of mesoderm by the mid- to late streak stage, at least 12 hours before their onset of expression in the neural tube in vivo at the early somite stage. In recombination explants, anterior mesendoderm from headfold stage embryos induces the expression of En-1 and En-2 in pre- to early streak ectoderm and in posterior ectoderm from headfold stage embryos. In contrast, posterior mesendoderm from embryos of the same stage does not induce En genes in pre- to early streak ectoderm but is able to induce expression of a general neural marker, neurofilament 160 × 10(3) M(r). These results provide the first direct evidence for a role of mesendoderm in induction and regionalization of neural tissue in mouse.

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development

Development ◽  
1999 ◽  
Vol 126 (18) ◽  
pp. 4005-4015 ◽  
Author(s):  
M. Weaver ◽  
J.M. Yingling ◽  
N.R. Dunn ◽  
S. Bellusci ◽  
B.L. Hogan
Keyword(s):  
Cell Types ◽  
Surfactant Protein ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Clara Cell ◽  
Mouse Lung ◽  
Marker Genes ◽  
Distal Marker ◽  
Morphogenetic Protein

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693–1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

scholarly journals Gap Junction–mediated Cell–Cell Communication Modulates Mouse Neural Crest Migration

1998 ◽  
Vol 143 (6) ◽  
pp. 1725-1734 ◽  
Author(s):  
G.Y. Huang ◽  
E.S. Cooper ◽  
K. Waldo ◽  
M.L. Kirby ◽  
N.B. Gilula ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neural Crest ◽  
Gap Junction ◽  
Heart Defects ◽  
Neural Crest Cells ◽  
Dominant Negative ◽  
Cardiac Neural Crest ◽  
Gap Junction Communication ◽  
Neural Crest Migration

Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in α1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for α1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing α1 connexins, and from α1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative α1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and α1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous α1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and α1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the α1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium— an elevation in the CMV43 mice vs. a reduction in the α1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non–neural crest– derived tissues. Overall, these findings suggest that gap junction communication mediated by α1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of α1 connexin function.

scholarly journals Effects of Shh and Noggin on neural crest formation demonstrate that BMP is required in the neural tube but not ectoderm

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 4919-4930 ◽  
Author(s):  
M.A. Selleck ◽  
M.I. Garcia-Castro ◽  
K.B. Artinger ◽  
M. Bronner-Fraser
Keyword(s):  
Neural Crest ◽  
Sonic Hedgehog ◽  
Neural Tube ◽  
Neural Crest Cells ◽  
Neural Plate ◽  
Bmp Signaling ◽  
Neural Tube Closure ◽  
Dorsal Neural Tube ◽  
Neural Ectoderm ◽  
Tube Closure

To define the timing of neural crest formation, we challenged the fate of presumptive neural crest cells by grafting notochords, Sonic Hedgehog- (Shh) or Noggin-secreting cells at different stages of neurulation in chick embryos. Notochords or Shh-secreting cells are able to prevent neural crest formation at open neural plate levels, as assayed by DiI-labeling and expression of the transcription factor, Slug, suggesting that neural crest cells are not committed to their fate at this time. In contrast, the BMP signaling antagonist, Noggin, does not repress neural crest formation at the open neural plate stage, but does so if injected into the lumen of the closing neural tube. The period of Noggin sensitivity corresponds to the time when BMPs are expressed in the dorsal neural tube but are down-regulated in the non-neural ectoderm. To confirm the timing of neural crest formation, Shh or Noggin were added to neural folds at defined times in culture. Shh inhibits neural crest production at early stages (0-5 hours in culture), whereas Noggin exerts an effect on neural crest production only later (5-10 hours in culture). Our results suggest three phases of neurulation that relate to neural crest formation: (1) an initial BMP-independent phase that can be prevented by Shh-mediated signals from the notochord; (2) an intermediate BMP-dependent phase around the time of neural tube closure, when BMP-4 is expressed in the dorsal neural tube; and (3) a later pre-migratory phase which is refractory to exogenous Shh and Noggin.

scholarly journals Building the Border: Development of the Chordate Neural Plate Border Region and Its Derivatives

2020 ◽  
Vol 11 ◽  
Author(s):  
Ankita Thawani ◽  
Andrew K. Groves
Keyword(s):  
Neural Crest ◽  
Signaling Pathways ◽  
Regulatory Networks ◽  
Neural Plate ◽  
Bmp Signaling ◽  
Border Region ◽  
Thin Strip ◽  
Morphogenetic Protein ◽  
Neural Plate Border ◽  
Spatio Temporal

The paired cranial sensory organs and peripheral nervous system of vertebrates arise from a thin strip of cells immediately adjacent to the developing neural plate. The neural plate border region comprises progenitors for four key populations of cells: neural plate cells, neural crest cells, the cranial placodes, and epidermis. Putative homologues of these neural plate border derivatives can be found in protochordates such as amphioxus and tunicates. In this review, we summarize key signaling pathways and transcription factors that regulate the inductive and patterning events at the neural plate border region that give rise to the neural crest and placodal lineages. Gene regulatory networks driven by signals from WNT, fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) signaling primarily dictate the formation of the crest and placodal lineages. We review these studies and discuss the potential of recent advances in spatio-temporal transcriptomic and epigenomic analyses that would allow a mechanistic understanding of how these signaling pathways and their downstream transcriptional cascades regulate the formation of the neural plate border region.

XBMPRII, a novel Xenopus type II receptor mediating BMP signaling in embryonic tissues

Development ◽  
1998 ◽  
Vol 125 (3) ◽  
pp. 431-442 ◽  
Author(s):  
A. Frisch ◽  
C.V. Wright
Keyword(s):  
Cell Fate ◽  
Organizer Region ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Mesoderm Induction ◽  
Type I ◽  
Type Ii ◽  
Common Component ◽  
Activin Signaling

Bone Morphogenetic Proteins (BMPs) are potent regulators of embryonic cell fate that are presumed to initiate signal transduction in recipient cells through multimeric, transmembrane, serine/threonine kinase complexes made up of type I and type II receptors. BMPRII was identified previously in mammals as the only type II receptor that binds BMPs, but not activin or TGFbeta, in vitro. We report the cloning and functional analysis in vivo of its Xenopus homolog, XBMPRII. XBMPRII is expressed maternally and zygotically in an initially unrestricted manner. Strikingly, XBMPRII transcripts then become restricted to the mesodermal precursors during gastrulation. Expression is lower in the dorsal organizer region, potentially providing a mechanism to suppress the actions of BMP4 on dorsally fated tissues. Similar to the results seen for a truncated type I BMP receptor (tBR), a dominant-negative form of XBMPRII (tBRII) can dorsalize ventral mesoderm, induce extensive secondary body axes, block mesoderm induction by BMP4 and directly neuralize ectoderm, strongly suggesting that XBMPRII mediates BMP signals in vivo. However, although both tBRII and tBR can induce partial secondary axes, marker analysis shows that tBRII-induced axes are more anteriorly extended. Additionally, coinjection of tBRII and tBR synergistically increases the incidence of secondary axis formation. A truncated activin type II receptor (deltaXAR1) is known to block both activin and BMP signaling in vivo. Here we show that such crossreactivity does not occur for tBRII, in that it does not affect activin signaling. Furthermore, our studies indicate that the full-length activin type II receptor (XAR1) overcomes a block in BMP4 signaling imposed by tBRII, implicating XAR1 as a common component of BMP and activin signaling pathways in vivo. These data implicate XBMPRII as a type II receptor with high selectivity for BMP signaling, and therefore as a critical mediator of the effects of BMPs as mesodermal patterning agents and suppressors of neural fate during embryogenesis.

Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle

2007 ◽  
Vol 292 (6) ◽  
pp. L1473-L1479 ◽  
Author(s):  
Moira Hagen ◽  
Karen Fagan ◽  
Wolfgang Steudel ◽  
Michelle Carr ◽  
Kirk Lane ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transgenic Mice ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Second Hit ◽  
Protein Receptor ◽  
Bmp Pathway

The majority of familial pulmonary arterial hypertension (PAH) cases are caused by mutations in the type 2 bone morphogenetic protein receptor (BMPR2). However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a “second hit.” There is substantial evidence from the literature implicating dysregulated inflammation, in particular the cytokine IL-6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL-6 in pulmonary tissues and conversely that IL-6 regulates the BMP pathway. We tested this in vivo using transgenic mice expressing an inducible dominant negative BMPR2 in smooth muscle, using mice injected with an IL-6-expressing virus, and in vitro using small interfering RNA (siRNA) to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL-6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38MAPK inhibitors. We also found that IL-6 in vivo caused a twofold increase in expression of the BMP signaling target Id1 and caused increased BMP activity in a luciferase-reporter assay in PA SMC. Thus we have shown both in vitro and in vivo a complete negative feedback loop between IL-6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit.

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.

Mechanisms of dorsal-ventral patterning in noggin-induced neural tissue

Development ◽  
1997 ◽  
Vol 124 (12) ◽  
pp. 2477-2488 ◽  
Author(s):  
A.K. Knecht ◽  
R.M. Harland
Keyword(s):  
Neural Tissue ◽  
Bmp Signaling ◽  
Cell Interactions ◽  
Dependent Manner ◽  
Low Doses ◽  
Morphogenetic Protein ◽  
High Doses ◽  
Dose Dependent ◽  
Cell Cell

We have investigated mechanisms of dorsal-ventral patterning of neural tissue, using Xenopus ectoderm neuralized by noggin protein. This tissue appears to be patterned dorsoventrally; cp1-1, a gene expressed in the dorsal brain, and etr-1, a gene largely excluded from the dorsal brain, are expressed in separate territories in noggin-treated explants (Knecht, A. K., Good, P. J., Dawid, I. B. and Harland, R. M. (1995) Development 121, 1927–1936). Here we show further evidence that this pattern represents a partial dorsal-ventral organization. Additionally, we test two mechanisms that could account for this pattern: a dose-dependent response to a gradient of noggin protein within the explant, and regulative cell-cell interactions. We show that noggin exhibits concentration-dependent effects, inducing cp1-1 at low doses but repressing it at high doses. Since noggin acts by antagonizing Bone Morphogenetic Protein (BMP) signaling, this result suggests that BMPs also may act in a dose-dependent manner in vivo. However, in the absence of a noggin gradient, regulative cell-cell interactions can also pattern the tissue. Such regulation is facilitated by increased motility of noggin-treated cells. Finally, the response of cells to both of these patterning mechanisms is ultimately controlled by a third process, the changing competence of the responding tissue.

scholarly journals Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling

2005 ◽  
Vol 169 (2) ◽  
pp. 309-320 ◽  
Author(s):  
Maurice Kléber ◽  
Hye-Youn Lee ◽  
Heiko Wurdak ◽  
Johanna Buchstaller ◽  
Martin M. Riccomagno ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Neural Crest ◽  
Bmp Signaling ◽  
Neural Crest Stem Cells ◽  
Stem Cell Maintenance ◽  
Intrinsic Cues ◽  
Sensory Neurogenesis ◽  
Canonical Wnt

Canonical Wnt signaling instructively promotes sensory neurogenesis in early neural crest stem cells (eNCSCs) (Lee, H.Y., M. Kléber, L. Hari, V. Brault, U. Suter, M.M. Taketo, R. Kemler, and L. Sommer. 2004. Science. 303:1020–1023). However, during normal development Wnt signaling induces a sensory fate only in a subpopulation of eNCSCs while other cells maintain their stem cell features, despite the presence of Wnt activity. Hence, factors counteracting Wnt signaling must exist. Here, we show that bone morphogenic protein (BMP) signaling antagonizes the sensory fate-inducing activity of Wnt/β-catenin. Intriguingly, Wnt and BMP act synergistically to suppress differentiation and to maintain NCSC marker expression and multipotency. Similar to NCSCs in vivo, NCSCs maintained in culture alter their responsiveness to instructive growth factors with time. Thus, stem cell development is regulated by combinatorial growth factor activities that interact with changing cell-intrinsic cues.

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