Modulation of Embryonic Intracellular Ca2+Signaling byWnt-5A

Slusarski, Diane C.; Yang-Snyder, Julia A.; Busa, William B.; Moon, Randall T.

doi:10.1006/dbio.1996.8463

Cited by 372 publications

(321 citation statements)

References 28 publications

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“…In addition to signaling via ROR2, it is likely that WNT5A has further functions because Wnt5a −/− mice have a more severe digit phenotype than Ror2 −/− mice (23). WNT5A is known to signal via Frizzled receptors to noncanonical pathways including the WNT/calcium pathway (26), which can also inhibit the β-catenin pathway (27). Thus it is conceivable that the truncated ROR2 protein might act as a scavenger for WNT5A, thus inhibiting WNT5A signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

Witte

Chan

Economides

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Elongation of the digit rays resulting in the formation of a defined number of phalanges is a process poorly understood in mammals, whereas in the chicken distal mesenchymal bone morphogenetic protein (BMP) signaling in the so-called phalanx-forming region (PFR) or digit crescent (DC) seems to be involved. The human brachydactylies (BDs) are inheritable conditions characterized by variable degrees of digit shortening, thus providing an ideal model to analyze the development and elongation of phalanges. We used a mouse model for BDB1 (Ror2 W749X/W749X ) lacking middle phalanges and show that a signaling center corresponding to the chick PFR exists in the mouse, which is diminished in BDB1 mice. This resulted in a strongly impaired elongation of the digit condensations due to reduced chondrogenic commitment of undifferentiated distal mesenchymal cells. We further show that a similar BMP-based mechanism accounts for digit shortening in a mouse model for the closely related condition BDA1 (Ihh E95K/E95K ), altogether indicating the functional significance of the PFR in mammals. Genetic interaction experiments as well as pathway analysis in BDB1 mice suggest that Indian hedgehog and WNT/β-catenin signaling, which we show is inhibited by receptor tyrosine kinase-like orphan receptor 2 (ROR2) in distal limb mesenchyme, are acting upstream of BMP signaling in the PFR. T he appendicular skeleton arises as a continuous cartilaginous condensation in the center of the limb bud that develops in a proximal to distal sequence. Distal outgrowth is under the control of fibroblast growth factor (FGF) signaling from the apical ectodermal ridge (AER), which accounts for proliferation in the subridge mesenchyme and prevents premature differentiation of mesenchymal cells, thus maintaining a progenitor pool. Cells leaving the range of AER-FGF signaling undergo differentiation into the mesenchymal cell lineages of the limb bud (1, 2).Evidence from the chick indicates that bone morphogenetic protein (BMP)/pSMAD1/5/8 signaling in a population of cells in front of the growing condensation, referred to as the phalanxforming region (PFR) or digit crescent (3, 4), is involved in the elongation of the digital rays. This work suggests that the PFR acts as a signaling center to drive distal elongation of the digit and thus determines the number of phalanges via commitment of distal mesenchymal cells to the cartilage condensation. However, evidence for such a mechanism in the mouse or human is missing.If a PFR-like structure exists in mammals, its failure is expected to cause digit malformation phenotypes such as digit shortening and loss of phalanges. This phenotypic spectrum is typical for a family of human inheritable malformations, the brachydactylies (BDs), which are characterized by the absence or reduction of individual phalanges and/or metacarpals (5). Intriguingly, several mutations causing human BDs (BDA2, BDB2, and BDC) affect the BMP pathway (5), which suggests the involvement of a PFRlike structure in digit growth.BD types A1 and B1...

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Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

Witte

Chan

Economides

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, integrindependent signaling pathways are involved in the activation of phosphatidyl inositol 3-kinase (PI3-kinase) through integrin-linked kinase (ILK) (Chen et al, 1996;King et al, 1997). In addition, recent studies have demonstrated that the Wnt signal also activates the phosphatidyl inositol signaling pathway (Slusarski et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

et al. 2004

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Motility-related protein-1 (MRP-1/CD9) is a transmembrane glycoprotein that has been implicated in cell adhesion, motility, proliferation, and differentiation. It has a functional role as a tumor metastatic suppressor. During tumor progression, a reduction of MRP-1/CD9 gene expression results in tumor cells with a high metastatic potential. However, the mechanism of action of MRP-1/CD9 is still unclear. We studied changes of gene expression in relation to MRP-1/CD9 gene transduction into tumor cell lines, HT1080 and A549, using microarray assays and real-time PCR. Consequently, we have demonstrated that MRP-1/ CD9 gene transduction can downregulate expression of several Wnt family genes, such as Wnt1, Wnt2b1 and Wnt5a, and their target genes, including WISP-1 (Wnt-1 induced secreted protein 1), WISP-3, c-Myc, vascular endothelial growth factor-A, and matrix metalloproteinase-26. Western blot analyses also showed that MRP-1/CD9 gene transduction downregulated expression of Wnt1 protein and its target proteins. In addition, a neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited the downregulation of Wnt signal pathways in MRP-1/CD9-transfected cells. The present study has revealed that the MRP-1/CD9 signal is located upstream of the Wnt signal pathways. Therefore, MRP-1/CD9 could suppress cell transformation including epithelial to mesenchymal transition through downregulation of Wnt1, and might suppress tumor metastasis through downregulation of Wnt5a.

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“…Genome sequencing projects have revealed that a large number of Wnt genes exist, including 7 Wnt genes in Drosophila and at least 19 Wnt genes in humans. 1 Wnt proteins function as growth factors and morphogens modulating cell growth and specifying cell fate.…”

mentioning

confidence: 99%

“…Embryonic studies in Xenopus and Zebrafish indicate that overexpression of Wnt5a results in an increased release of intracellular calcium (19). Wnt5a overexpression can also lead to increased activation of classical protein kinase C and calmodulin-dependent protein kinase II (CamKII) (20,21), two calcium-responsive serine threonine kinases.…”

mentioning

confidence: 99%

Multiple Mechanisms for Wnt11-mediated Repression of the Canonical Wnt Signaling Pathway

Maye

Zheng

et al. 2004

Journal of Biological Chemistry

124

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The effect of a noncanonical Wnt, Wnt11, on canonical Wnt signaling stimulated by Wnt1 and activated forms of LRP5 (low density lipoprotein receptor-related protein-5), Dishevelled1 (Dvl1), and ␤-catenin was examined in NIH3T3 cells and P19 embryonic carcinoma cells. Wnt11 repressed Wnt1-mediated activation of LEF-1 reporter activity in both cell lines. However, Wnt11 was unable to inhibit canonical signaling activated by LRP5, Dvl1, or ␤-catenin in NIH3T3 cells, although it could in P19 cells. In addition, Wnt11-mediated inhibition of canonical signaling in NIH3T3 cells is ligand-specific; Wnt11 could effectively repress canonical signaling activated by Wnt1, Wnt3, or Wnt3a but not by Wnt7a or Wnt7b. Coculture experiments with NIH3T3 cells showed that the co-expression of Wnt11 with Wnt1 was not an essential requirement for the inhibition, suggesting receptor competition as a possible mechanism. Moreover, in both cell types, elevation of intracellular Ca 2؉ levels, which can result from Wnt11 treatment, led to the inhibition of canonical signaling. This result suggests that Wnt11 might not be able to signal in NIH3T3. Furthermore, P19 cells were found to express both endogenous canonical Wnts and Wnt11. Knockdown of Wnt11 expression using siRNA resulted in increased LEF-1 reporter activity, thus indicating that Wnt11-mediated suppression of canonical signaling exists in vivo.The Wnt gene family encodes for a conserved class of secreted signaling molecules and is considered one of the major gene families essential for proper embryonic patterning and organogenesis. Genome sequencing projects have revealed that a large number of Wnt genes exist, including 7 Wnt genes in Drosophila and at least 19 Wnt genes in humans. 1 Wnt proteins function as growth factors and morphogens modulating cell growth and specifying cell fate. Early segment polarity screens in Drosophila resulted in the identification of key components of a "canonical" Wnt signaling pathway (2). Since then, extensive research on the canonical pathway has identified several genes, the gene products of which interact in a complex series of mechanisms that ultimately regulate the canonical pathway.At the cell surface, Wnt proteins activate the pathway through binding a receptor complex consisting of Frizzled, a seven transmembrane receptor, and its co-receptor LRP-5/6 2 (low density lipoprotein receptor-related protein-5/6) (3-5). Intracellular mediators of the canonical pathway include Dishevelled and ␤-catenin (6, 7), which promote pathway activation, and Axin and GSK-3␤ (8, 9), which negatively regulate the pathway. In the absence of Wnt ligand, cytoplasmic levels of ␤-catenin protein remain low, as a result of its association with GSK-3␤ and Axin, which target it for proteolytic degradation (10). Upon Wnt ligand binding, GSK-3␤ is inhibited, and cytoplasmic levels of ␤-catenin protein increase (11) and subsequently translocate into the nucleus, where it functions as a transcriptional co-activator, commonly associating with members of the LEF/TCF family...

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Modulation of Embryonic Intracellular Ca2+Signaling byWnt-5A

Cited by 372 publications

References 28 publications

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

Multiple Mechanisms for Wnt11-mediated Repression of the Canonical Wnt Signaling Pathway

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