<i>Dkk1</i>and<i>Wnt3</i>interact to control head morphogenesis in the mouse

Lewis, Samara E.; Khoo, Poh-Lynn; Young, Roy E.; Steiner, Kirsten A.; Wilcock, C. C.; Mukhopadhyay, Mahua; Westphal, Heiner; Jamieson, Robyn V; Robb, Lorraine; Tam, Patrick

doi:10.1242/dev.018853

Cited by 99 publications

(117 citation statements)

References 66 publications

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“…In vertebrates, Wnt antagonists, such as DKK, are expressed anteriorly to repress Wnt signaling in the head (24). In insects, such antagonizing factors have yet to be found, and repression of Wnt signaling has not been implicated in anterior development.…”

Section: Discussionmentioning

confidence: 99%

Asymmetrically expressed axin required for anterior development in Tribolium

Posnien

Bolognesi

et al. 2012

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

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Canonical Wnt signaling has been implicated in an AP axis polarizing mechanism in most animals, despite limited evidence from arthropods. In the long-germ insect, Drosophila, Wnt signaling is not required for global AP patterning, but in short-germ insects including Tribolium castaneum, loss of Wnt signaling affects development of segments in the growth zone but not those defined in the blastoderm. To determine the effects of ectopic Wnt signaling, we analyzed the expression and function of axin, which encodes a highly conserved negative regulator of the pathway. We found Tc-axin transcripts maternally localized to the anterior pole in freshly laid eggs. Expression spread toward the posterior pole during the early cleavage stages, becoming ubiquitous by the time the germ rudiment formed. Tc-axin RNAi produced progeny phenotypes that ranged from mildly affected embryos with cuticles displaying a graded loss of anterior structures, to defective embryos that condensed at the posterior pole in the absence of serosa. Altered expression domains of several blastodermal markers indicated anterior expansion of posterior fates. Analysis of other canonical Wnt pathway components and the expansion of Tc-caudal expression, a Wnt target, suggest that the effects of Tc-axin depletion are mediated through this pathway and that Wnt signaling must be inhibited for proper anterior development in Tribolium. These studies provide unique evidence that canonical Wnt signaling must be carefully regulated along the AP axis in an arthropod, and support an ancestral role for Wnt activity in defining AP polarity and patterning in metazoan development.A-P axis patterning | short-germ segmentation | anterior patterning | maternal determination

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Section: Discussionmentioning

confidence: 99%

Asymmetrically expressed axin required for anterior development in Tribolium

Posnien

Bolognesi

et al. 2012

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

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“…1B), suggesting that negative modulation of signalling activity is a prerequisite for normal development of the head. In the mouse, embryos lacking Dkk1 activity display ectopic and elevated WNT signalling activity in precursor tissues of the embryonic head and fail to form brain and head structures (Lewis et al, 2008;Mukhopadhyay et al, 2001), whereas reduced Dkk1 activity in the hypomorphic Dkk1-doubleridge mutant is associated with head malformation (MacDonald et al, 2004). Analysis of the phenotype of compound mutant embryos has revealed that the severity of head truncation defects caused by loss of Dkk1 function might be enhanced by reducing the gene dosage of Gsc (Lewis et al, 2007), which acts to repress the transcription of WNT ligand genes (Yao and Kessler, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of the phenotype of compound mutant embryos has revealed that the severity of head truncation defects caused by loss of Dkk1 function might be enhanced by reducing the gene dosage of Gsc (Lewis et al, 2007), which acts to repress the transcription of WNT ligand genes (Yao and Kessler, 2001). By contrast, reducing the level of Wnt3 activity is sufficient to allow normal head morphogenesis in some embryos that completely lack Dkk1 activity (Lewis et al, 2008). A precedent study has also shown that the loss of Dkk1 antagonist function might be compensated for by reduction of the function of the LRP6 co-receptor (MacDonald et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Stringent requirement of a proper level of canonical WNT signalling activity for head formation in mouse embryo

et al. 2011

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SUMMARYIn mouse embryos, loss of Dickkopf-1 (DKK1) activity is associated with an ectopic activation of WNT signalling responses in the precursors of the craniofacial structures and leads to a complete truncation of the head at early organogenesis. Here, we show that ENU-induced mutations of genes coding for two WNT canonical pathway factors, the co-receptor LRP6 and the transcriptional co-activator -catenin, also elicit an ectopic signalling response and result in loss of the rostral tissues of the forebrain. Compound mutant embryos harbouring combinations of mutant alleles of Lrp6, Ctnnb1 and Dkk1 recapitulate the partial to complete head truncation phenotype of individual homozygous mutants. The demonstration of a synergistic interaction of Dkk1, Lrp6 and Ctnnb1 provides compelling evidence supporting the concepts that (1) stringent regulation of the level of canonical WNT signalling is necessary for head formation, (2) activity of the canonical pathway is sufficient to account for the phenotypic effects of mutations in three different components of the signal cascade and (3) rostral parts of the brain and the head are differentially more sensitive to canonical WNT signalling and their development is contingent on negative modulation of WNT signalling activity.

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“…Dkk1, which antagonizes Wnt signaling by binding to Lrp5/6, is initially expressed in a crescent-shaped domain around the AVE, and later in the primitive streak-derived anterior mesendoderm (AME) (Mukhopadhyay et al 2001;Kimura-Yoshida et al 2005). In Dkk1 -/-null mutants, Wnt reporter expression expands anteriorly from E7.0 and head truncation occurs by E9.5 (Mukhopadhyay et al 2001;Lewis et al 2008). Chimera analysis indicated that AVEderived Dkk1 is dispensable, whereas AME-derived Dkk1 is sufficient for anterior head patterning (Mukhopadhyay et al 2001).…”

Section: Wnt Signaling Suppression In Anterior Patterningmentioning

confidence: 99%

“…Chimera analysis indicated that AVEderived Dkk1 is dispensable, whereas AME-derived Dkk1 is sufficient for anterior head patterning (Mukhopadhyay et al 2001). Interestingly, the head truncation defect in Dkk1 -/-mutants can be partially suppressed by halving the dosage of Wnt3 (Lewis et al 2008), indicating that a major function of Dkk1 is to modulate Wnt3 induced Wnt signaling. Furthermore, proper anterior patterning also requires inhibition of b-catenin mediated transactivation by ICAT (Inhibitor of b-catenin and T cell factor), an 81 amino acid protein that disrupts the interaction between b-catenin and TCF.…”

Section: Wnt Signaling Suppression In Anterior Patterningmentioning

confidence: 99%