Dickkopf genes are co-ordinately expressed in mesodermal lineages

Abstract

Dickkopf-1 (dkk-1) is member of a novel family of secreted proteins and functions in head induction during Xenopus embryogenesis, acting as a potent inhibitor of Wnt signalling. Here we report: (1) the isolation of two additional murine members of the dkk family, dkk-2 and dkk-3; and (2) analysis of adult and embryonic gene expression of mouse dkk-1,-2, and -3, Xenopus dkk-1 as well as chicken dkk-3. Comparative developmental analyses of the dkk-1, dkk-2 and dkk-3 in mice indicate that these genes are both temporally and spatially regulated. They define overlapping deep domains in mesenchymal lineages suggesting a co-ordinated mode of action. All dkks show distinct and elevated expression patterns in tissues that mediate epithelial- mesenchyme transformations suggesting that they may participate in heart, tooth, hair and whisker follicle, limb and bone induction. In the limb buds expression of these genes are found in regions of programmed cell death. In a given organ, dkk-1 tends to be the earliest member expressed. Comparison with Xenopus dkk-1 and chicken dkk-3 shows evolutionarily conserved expression patterns. Our observations indicate that dkk genes constitute a new family of secreted proteins that may mediate inductive interactions between epithelial and mesenchymal cells.

Function and biological roles of the Dickkopf family of Wnt modulators

“…Furthermore, there is strong enhancement of head defects when both Dkk1 and Krm1,2 are inhibited . This argues for a functional interaction between these proteins in vivo and is consistent with overlapping expression patterns during development (Monaghan et al, 1999;Nakamura et al, 2001;Davidson et al, 2002). However, it is likely that Dkks are also able to modulate Wnt/b-catenin signaling in the absence of Krm, since Dkk1 can directly block the Lrp6-Wnt interaction (Semenov et al, 2001) (Figure 2b).…”

“…These Dkks display suggestive expression patterns in eye primordia, including pigmented epithelium, choroid and retina (Monaghan et al, 1999). Wnt/b-catenin signaling plays an important role in various stages of eye formation, including early patterning (Esteve and Bovolenta, 2006), retinal development (Van Raay and Vetter, 2004), lens formation (Lovicu and McAvoy, 2005) and eye angiogenesis (Niehrs, 2004a).…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…During embryogenesis in mice, Dkk-1 expression is temporally and spatially regulated, which gives Dkk-1 the potential to regulate anterior-posterior axial pattern formation, including head induction. At later stages of development and after birth, Dkk-1 expression is detected in the aorta and retinal vasculature, respectively (64,65). Dkk-1 expression is also observed in human endothelial cells cultured in vitro.…”

Bone mass is inversely proportional to Dkk1 levels in mice

“…The residual Dkk1 expression in Dkk1 d/d or Dkk1 d/− mice is sufficient for head development and survival to adulthood. In addition to being widely and dynamically expressed during embryonic development, Dkk1 is also predominantly expressed in adult bone tissues [38,39]. Similar to the expression of SOST, Dkk1 is present in the mature osteoblast/osteocyte, suggesting that DKK1 may regulate bone homeostasis [40].…”