Dickkopf1 (Dkk1) is a secreted protein that acts as a Wnt inhibitor and, together with BMP inhibitors, is able to induce the formation of ectopic heads in Xenopus. Here, we show that Dkk1 null mutant embryos lack head structures anterior of the midbrain. Analysis of chimeric embryos implicates the requirement of Dkk1 in anterior axial mesendoderm but not in anterior visceral endoderm for head induction. In addition, mutant embryos show duplications and fusions of limb digits. Characterization of the limb phenotype strongly suggests a role for Dkk1 both in cell proliferation and in programmed cell death. Our data provide direct genetic evidence for the requirement of secreted Wnt antagonists during embryonic patterning and implicate Dkk1 as an essential inducer during anterior specification as well as a regulator during distal limb patterning.

The Dkk family of secreted cysteine-rich proteins regulates Wnt/β-catenin signaling by interacting with the Wnt co-receptor Lrp5/6. Here, we show that Dkk2-mediated repression of the Wnt/β-catenin pathway is essential to promote differentiation of the corneal epithelial progenitor cells into a non-keratinizing stratified epithelium. Complete transformation of the corneal epithelium into a stratified epithelium that expresses epidermal-specific differentiation markers and develops appendages such as hair follicles is achieved in the absence of the Dkk2 gene function. We show that Dkk2 is a key regulator of the corneal versus epidermal fate of the ocular surface epithelium.

dickkopf (dkk) genes encode a small family of secreted Wnt antagonists, except for dkk3, which is divergent and whose function is poorly understood. Here, we describe the generation and characterization of dkk3 mutant mice. dkk3-deficient mice are viable and fertile. Phenotypic analysis shows no major alterations in organ morphology, physiology, and most clinical chemistry parameters. Since Dkk3 was proposed to function as thyroid hormone binding protein, we have analyzed deiodinase activities, as well as thyroid hormone levels. Mutant mice are euthyroid, and the data do not support a relationship of dkk3 with thyroid hormone metabolism. Altered phenotypes in dkk3 mutant mice were observed in the frequency of NK cells, immunoglobulin M, hemoglobin, and hematocrit levels, as well as lung ventilation. Furthermore, dkk3-deficient mice display hyperactivity.The Dickkopf family of secreted proteins consists of four members, which share two conserved cysteine-rich domains (12,24). The hallmark of Dkk proteins is that they function as Wnt antagonists or agonists by binding to and inhibiting or activating the Wnt coreceptor LRP6 (1, 31, 45). They show regionalized expression during vertebrate embryogenesis (5,10,13,18,20,33,46). Dkk1 is the best-characterized member of the family. It acts as an embryonic head inducer, and when overexpressed it will induce extra heads in Xenopus and zebra fish (6,12,18,22,36,46). dkk1 mutant mice are embryonic lethal, and embryos lack anterior head structure and display fused digits (36). dkk2 mouse mutants are viable but show bone defects (28). Little is known about the biological role of dkk4.By a number of criteria, dkk3 appears as a divergent member of the dkk family. (i) By DNA sequence similarity, vertebrate dkk1, -2, and -4 are more related to each other than they are to dkk3 (12). (ii) Hydra has two dkk genes, one related to vertebrate dkk1, -2, and -4 (16) and one related to vertebrate dkk3 (9). This suggests an ancient phylogenetic separation between these family members, where dkk1, -2, and -4 but not dkk3 arose by gene duplication from an ancestral dkk (16). (iii) Soggy is a protein of unknown function with sequence similarity to dkk3 but not to other dkk genes (24). The similarity is most pronounced outside the two conserved Dkk cysteine-rich domains, raising the possibility that the gene arose from an ancestral dkk3 precursor. (iv) Unlike Dkk1, -2, and -4, Dkk3 does not act as a Wnt modulator (24,29,55). While all other tested Dkk proteins bind to and modulate the Wnt receptor LRP6, as well as the Dkk coreceptor Kremen, Dkk3 has no affinity to these transmembrane proteins (7,30,32,33), and no other proteins are known to interact with it.Like other dkk members, dkk3 is expressed during vertebrate development in suggestive patterns in many organs (7,33). Prominent expression of dkk3 is observed in the brain and in fibroblasts of adult rodents (17,24,34,37,56) and in the human adrenal cortex (50).

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