From solid roots to rustling leaves E-cadherin and β-catenin across the branches of hematopoiesis in evolution

Anemia, affecting one third of the global population, is caused by a shortage of (functional) red blood cells. Understanding the molecular mechanisms underlying both normal and emergency red cell production, also known as homeostatic and stress erythropoiesis, is crucial for developing advanced anemia treatments. Interestingly, the epithelial adhesion molecule and tumor suppressor E-cadherin has been found to be expressed in human erythroid progenitor cells. While E-cadherin’s function in epithelia is well-established, its role in erythroid progenitors is unclear. This dissertation focuses on the role of E-cadherin and its binding partner β-catenin, an important signaling molecule, in regulating erythroid cell behavior during homeostatic and stress erythropoiesis.
While E-cadherin is highly evolutionary conserved, mice do not express E-cadherin in the erythroid, but basophil lineage. Interestingly, rats exhibit a closer resemblance to humans in erythropoiesis. We found that rats erythroid progenitors do express E-cadherin. Moreover, both E-cadherin and β-catenin expression increase during anemia in rats, suggesting a functional role in erythroid turnover. Further in-vitro analysis reveals that E-cadherin stabilizes β-catenin at the cell membrane, but it remains unknown how E-cadherin regulates β-catenin signaling. β-catenin accumulation in erythroid progenitors does not immediately activate its canonical target genes, but it interacts with FOXO3, a protein essential for erythroid terminal differentiation during stress erythropoiesis. This interaction potentially facilitates erythroid turnover upon anemia.
Overall, this research highlights the importance of carefully selecting animal models for mammalian processes and sheds light on the intricate interaction between E-cadherin and β-catenin governing erythropoiesis.