Author Correction: Gap junction protein Connexin-43 is a direct transcriptional regulator of N-cadherin in vivo.

The original version of this Article contained an error in the spelling of the author Alexandra Schambony, which was incorrectly given as Alexandra Schambon. This has now been corrected in both the PDF and HTML versions of the Article.

Gap junction protein Connexin-43 is a direct transcriptional regulator of N-cadherin in vivo.

Connexins are the primary components of gap junctions, providing direct links between cells under many physiological processes. Here, we demonstrate that in addition to this canonical role, Connexins act as transcriptional regulators. We show that Connexin 43 (Cx43) controls neural crest cell migration in vivo by directly regulating N-cadherin transcription. This activity requires interaction between Cx43 carboxy tail and the basic transcription factor-3, which drives the translocation of Cx43 tail to the nucleus. Once in the nucleus they form a complex with PolII which directly binds to the N-cadherin promoter. We found that this mechanism is conserved between amphibian and mammalian cells. Given the strong evolutionary conservation of connexins across vertebrates, this may reflect a common mechanism of gene regulation by a protein whose function was previously ascribed only to gap junctional communication.

The phosphatase Pgam5 antagonizes Wnt/ß-Catenin signaling in embryonic anterior-posterior axis patterning.

The scaffold protein Dishevelled is a central intracellular component of Wnt signaling pathways. Various kinases have been described that regulate and modulate Wnt signaling through phosphorylation of Dishevelled. However, besides general protein phosphatases 1 and 2 (PP1 and PP2), no specific protein phosphatases have been identified. Here, we report on the identification and functional characterization of the protein phosphatase Pgam5 in vitro and in vivo in Xenopus Pgam5 is a novel antagonist of Wnt/ß-Catenin signaling in human cells and Xenopus embryogenesis. In early development, Pgam5 is essential for head formation, and for establishing and maintaining the Wnt/ß-Catenin signaling gradient that patterns the anterior-posterior body axis. Inhibition of Wnt/ß-Catenin signaling and developmental function depend on Pgam5 phosphatase activity. We show that Pgam5 interacts with Dishevelled2 and that Dishevelled2 is a substrate of Pgam5. Pgam5 mediates a marked decrease in Dishevelled2 phosphorylation in the cytoplasm and in the nucleus, as well as decreased interaction between Dishevelled2, Tcf1 and ß-Catenin, indicating that Pgam5 regulates Dishevelled function upstream and downstream of ß-Catenin stabilization.

ROR-Family Receptor Tyrosine Kinases.

ROR-family receptor tyrosine kinases form a small subfamily of receptor tyrosine kinases (RTKs), characterized by a conserved, unique domain architecture. ROR RTKs are evolutionary conserved throughout the animal kingdom and act as alternative receptors and coreceptors of WNT ligands. The intracellular signaling cascades activated downstream of ROR receptors are diverse, including but not limited to ROR-Frizzled-mediated activation of planar cell polarity signaling, RTK-like signaling, and antagonistic regulation of WNT/ß-Catenin signaling. In line with their diverse repertoire of signaling functions, ROR receptors are involved in the regulation of multiple processes in embryonic development such as development of the axial and paraxial mesoderm, the nervous system and the neural crest, the axial and appendicular skeleton, and the kidney. In humans, mutations in the ROR2 gene cause two distinct developmental syndromes, recessive Robinow syndrome (RRS; MIM 268310) and dominant brachydactyly type B1 (BDB1; MIM 113000). In Robinow syndrome patients and animal models, the development of multiple organs is affected, whereas BDB1 results only in shortening of the distal phalanges of fingers and toes, reflecting the diversity of functions and signaling activities of ROR-family RTKs. In this chapter, we give an overview on ROR receptor structure and function. We discuss their signaling functions and role in vertebrate embryonic development with a focus on those developmental processes that are affected by mutations in the ROR2 gene in human patients.

Distinct functionality of dishevelled isoforms on Ca2+/calmodulin-dependent protein kinase 2 (CamKII) in Xenopus gastrulation.

Wnt ligands trigger the activation of a variety of ß-catenin-dependent and ß-catenin-independent intracellular signaling cascades. Despite the variations in intracellular signaling, Wnt pathways share the effector proteins frizzled, dishevelled, and ß-arrestin. It is unclear how the specific activation of individual branches and the integration of multiple signals are achieved. We hypothesized that the composition of dishevelled-ß-arrestin protein complexes contributes to signal specificity and identified CamKII as an interaction partner of the dishevelled-ß-arrestin protein complex by quantitative functional proteomics. Specifically, we found that CamKII isoforms interact differentially with the three vertebrate dishevelled proteins. Dvl1 is required for the activation of CamKII and PKC in the Wnt/Ca(2+) pathway. However, CamKII interacts with Dvl2 but not with Dvl1, and Dvl2 is necessary to mediate CamKII function downstream of Dvl1 in convergent extension movements in Xenopus gastrulation. Our findings indicate that the different Dvl proteins and the composition of dishevelled-ß-arrestin protein complexes contribute to the specific activation of individual branches of Wnt signaling.