Disease relevance of Dkk1

• Decreasing expression of Dkk1 results in hemivertebral fusions in progressively more anterior positions, with severity increasing from tail kinks to spinal curvature [1].
• Structural, dynamic, and cellular analysis of bone remodeling in Dkk1(+/-) mice showed an increase in all bone formation parameters, with no change in bone resorption, leading to a marked increase in bone mass [2].
• Adenovirus Dkk1 (Ad Dkk1) treatment of adult mice repressed expression of the Wnt target genes CD44 and EphB2 within 2 days in both small intestine and colon, indicating an extremely broad role for Wnt signaling in the maintenance of adult gastrointestinal gene expression [3].
• Whereas decreased Dkk1 expression at later time points (>10 days) was followed by crypt and villus regeneration, which was consistent with a reversible process, substantial mortality ensued from colitis and systemic infection [3].
• Expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the Wnt pathway, was induced in the hippocampus of gerbils and rats subjected to transient global cerebral ischemia as well as in cultured cortical neurons challenged with an excitotoxic pulse [4].

High impact information on Dkk1

• Wnt/beta-catenin signalling is inhibited by the secreted protein Dickkopf1 (Dkk1), a member of a multigene family, which induces head formation in amphibian embryos [5].
• Here we describe dickkopf-1 (dkk-1), which encodes Dkk-1, a secreted inducer of Spemann's organizer in Xenopus and a member of a new protein family [6].
• Loss of Hex function blocks both endogenous heart development and ectopic heart induction by Dkk-1 [7].
• A screen for downstream mediators revealed that Dkk-1 and other inhibitors of the canonical Wnt pathway induce the homeodomain transcription factor Hex, which is normally expressed in endoderm underlying the presumptive cardiac mesoderm in amphibian, bird, and mammalian embryos [7].
• Dkk1 and noggin cooperate in mammalian head induction [8].

Biological context of Dkk1

• Expression of Dkk1 from the doubleridge allele ranges from 35% of wild-type level in E7.0 head to <1% of wild type in E13.5 tail. doubleridge homozygotes and doubleridge/null compound heterozygotes are viable [1].
• We have cloned the doubleridge transgene insertion site and demonstrate that doubleridge acts in cis from a distance of 150 kb to reduce the expression of dickkopf 1 (Dkk1), the secreted Wnt antagonist [1].
• Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass [2].
• To determine the role of Dkk1 in vivo and overcome the embryonic lethality of homozygous deletion, we studied the bone phenotype in heterozygous Dkk1-deficient mice [2].
• During molar morphogenesis Dkk1 was detected in the dental mesenchyme, including the preodontoblasts [9].

Anatomical context of Dkk1

• An allelic series combining the wild-type, doubleridge and null alleles of Dkk1 demonstrates the effect of varying Dkk1 concentration on development of limb, head and vertebrae [1].
• In addition, the effect of Dkk1 osteoblast was studied in MC3T3-E1 cells by means of recombinant protein [2].
• Using rat primary calvaria cells, we studied the effect of retroviral expression of Dkk1 on osteoblast differentiation [2].
• Dkk1 expression also increased adipocyte differentiation in these cell cultures [2].
• Dkk1 was prominently expressed in the distal, incisor-bearing mesenchyme area of the mandibular process during the initial stages of tooth formation [9].

Associations of Dkk1 with chemical compounds

• Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid [10].
• Treatment of ischemic animals with either Dkk-1 antisense oligonucleotides or lithium ions (which rescue the Wnt pathway acting downstream of the Dkk-1 blockade) protected vulnerable hippocampal neurons against ischemic damage [4].
• The C-terminal Cys rich region was well conserved among vertebrate Dkk1 orthologs [11].

Physical interactions of Dkk1

• En1 and Wnt7a interact with Dkk1 during limb development in the mouse [12].

Regulatory relationships of Dkk1

• Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts; moreover, TOPGAL(+) (Wnt reporter); CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression [13].
• Interestingly, Bmp-4 only activates Dkk-1 when it concomitantly induces apoptosis [14].
• The Wnt antagonist Dickkopf-1 is regulated by Bmp signaling and c-Jun and modulates programmed cell death [14].

Other interactions of Dkk1

• Similarly, the anterior head truncation characteristic of Dkk1 null mice was rescued by reduction of Lrp6 [1].
• Postnatally, Dkk1 was prominently expressed in the preodonto- and odontoblasts, while Dkk3 mRNAs were transiently seen in the preameloblasts before the onset of enamel matrix secretion [9].
• We demonstrated interaction between Dkk1 and the Wnt coreceptors Lrp5 and Lrp6 by analysis of several types of double mutants [1].
• The Dickkopf (Dkk) family and Mmp9 are important for apoptosis and a number of other developmental processes [15].
• Reducing Dkk1 expression in Dkk1d/+Wnt7a-/- double mutants prevented digit loss, indicating that Wnt7a acts through the canonical pathway during limb development [12].

Analytical, diagnostic and therapeutic context of Dkk1

• To determine the role of Wnt signaling in early lung development, E11.5 organ cultures were treated with recombinant DKK1 [16].
• 5. Using double-whole mount in situ hybridization we show that the posterior Dkk-1 expression domain initially overlaps with that of Shh, one of the key signalling molecules in limb development [17].
• TUNEL assay revealed that in tumors originating from cells transduced with DKK-1 apoptotic cells were detected along the border of necrotic and viable areas of the tumors indicating significant increase in apoptotic process [18].
• Immunohistochemical technique was employed to determine the location of DKK-1 protein in endometrium, and semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) was utilized to determine the levels of DKK-1 mRNA [19].

References