En1 and Wnt7a interact with Dkk1 during limb development in the mouse

Abstract

Wnt signaling plays an essential role in induction and development of the limb. Missing digits are one consequence of the reduced Wnt signaling in Wnt7a null mice, while extra digits result from excess Wnt signaling in mice null for the Wnt antagonist Dkk1. The extra digits and expanded apical ectodermal ridge (AER) of Dkk1-deficient mice closely resemble En1 null mice. To evaluate the in vivo interaction between En1 and the canonical Wnt signaling pathway, we generated double and triple mutants combining the hypomorphic doubleridge allele of Dkk1 with null alleles of En1 and Wnt7a. Reducing Dkk1 expression in Dkk1d/+Wnt7a-/- double mutants prevented digit loss, indicating that Wnt7a acts through the canonical pathway during limb development. Reducing Dkk1 levels in Dkk1d/dEn1-/- double mutants resulted in severe phenotypes not seen in either single mutant, including fused bones in the autopod, extensive defects of the zeugopod, and loss of the ischial bone. The subsequent elimination of Wnt7a in Dkk1d/dEn1-/-Wnt7a-/- triple mutants resulted in correction of most, but not all, of these defects. The failure of Wnt7a inactivation to completely correct the limb defects of Dkk1d/dEn1-/- double mutants indicates that Wnt7a is not the only gene regulated by En1 during development of the mouse limb.

Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers

“…Specifically, the promoter-associated CpG island of genes EN1, SCTR, and INHBB exhibited increased DNA methylation in prostate cancer cell lines compared with the normal prostate cell line PrEC, and EN1 and SCTR were found to be significantly methylated in clinical prostate cancer cells. The EN1 gene codes for a homeobox transcription factor, which interacts with the WNT signaling pathway (45) and is essential for development (46). SCTR encodes the secretin receptor, a G-protein-coupled receptor that is also hypermethylated and downregulated in pancreatic (47) and colorectal cancer (29).…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…Conversely, overactivation of Wnt signaling by expression of a gain-of-function mutation of b-catenin results in expansion of the AER (Soshnikova et al 2003). An expansion of the AER is observed in both Dkk1-null and hypomorphic Dkk1 d/d mutants, suggesting a genetic interaction with Wnt3a (Mukhopadhyay et al 2001;Adamska et al 2004;MacDonald et al 2004). In addition to AER expansion, Dkk1-null and Dkk1 d/d mutants display postaxial polysyndactyly in the forelimbs (Mukhopadhyay et al 2001;MacDonald et al 2004), and normal digit numbers are restored in MacDonald et al 2004).…”

Function and biological roles of the Dickkopf family of Wnt modulators

“…Conversely, overactivation of Wnt signaling by expression of a gain-of-function mutation of b-catenin results in expansion of the AER (Soshnikova et al, 2003). An expansion of the AER is observed in both Dkk1 null and hypomorphic Dkk1 d/d mutants, suggesting a genetic interaction with Wnt3 (Mukhopadhyay et al, 2001;Adamska et al, 2004;MacDonald et al, 2004). In the control of the AER, Wnt3 lies upstream of BMP ligands (Barrow et al, 2003) and Dkk1 interacts with BMPs in this context, as they can mutually induce each others expression (Mukhopadhyay et al, 2001;Grotewold and Ru¨ther, 2002).…”