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Figure 6


Fig. 6. The scheme of genetic interaction and the requirement of Dkk1 and Wnt3 activity in anterior morphogenesis. (A) The modulation of WNT3 signalling by the antagonistic action of DKK1 maintains a correct level of patterning activity. (B) Halving the dose of both genes in the Dkk1+/-;Wnt3+/- embryo would theoretically produce a `balanced' level of patterning activity but at a reduced level (thinner arrow and inhibitory connector). (C) Because of the requirement of WNT3 signalling to regulate the expression of Dkk1, the reduced level of signalling associated with the Wnt3+/- genotype and the loss of one copy of transcription target Dkk1 gene in the Dkk1+/-;Wnt3+/- embryo have resulted in a reduction of DKK1 activity to below the heterozygous (Dkk1+/-) level, which may be inadequate for antagonizing WNT3 signalling (dotted inhibitory connector). This may lead to an unbalanced (and reduced) WNT3 signalling activity (broken arrow) that disrupts head morphogenesis in the Dkk1+/-;Wnt3+/- embryos. (D-H) The schematic profile of agonist (WNT3) and antagonist (DKK1) activity (red, WNT3 signal; green, DKK1 activity; white, no activity; shaded, reduced activity) in embryos of different Dkk1 and Wnt3 genotypes, correlated with the pattern of WNT reporter (TOPGal) expression in the E7.75 and E9.5 embryos, and the phenotypic consequences. (D) A balanced Dkk1 and Wnt3 activity in the wild-type embryo enables normal pattering and morphogenesis of anterior (head) structures. (E,F) The unbalanced agonist and antagonist activity leads to an elevated WNT signalling (revealed by the expanded TOPGal expression domain) and abnormal phenotypic outcome in embryos of (E) Dkk1-/-;Wnt3+/+ (Dkk1 null) and (F) Dkk1+/-;Wnt3+/- (compound heterozygous) embryos. (G) In Dkk1-/-;Wnt3+/- (rescued) embryos, the TOPGal expression domain is very similar to that of (D) the wild-type embryo. (H) Wnt3-null embryos do not develop beyond gastrulation and show no TOPGal expression when examined at E7.75 or E9.0, which may indicate a complete shutdown of WNT signalling function owing to arrested development.