RESUMO
Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand signaling through one transcription factor promoted two seemingly contradictory cellular processes was unclear. In this study, we show that Wnt9b/beta-catenin signaling alone is sufficient to promote both renewal and differentiation. Moreover, we show that discrete levels of beta-catenin can promote these two disparate fates, with low levels fostering progenitor renewal and high levels driving differentiation. These results provide insight into how Wnt9b regulates distinct target genes that balance nephron progenitor renewal and differentiation.
Assuntos
Néfrons/fisiologia , beta Catenina/metabolismo , beta Catenina/fisiologia , Animais , Diferenciação Celular/genética , Regulação da Expressão Gênica/genética , Rim/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Néfrons/embriologia , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Células-Tronco/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologiaRESUMO
Lineage tracing has resulted in fundamental discoveries in kidney development and disease and remains a powerful technique to study mechanisms of organogenesis, homeostasis, and repair/regeneration. Following decades of research on the cellular and molecular regulation of renal organogenesis, the kidney has become one of the most well-characterized organs, resulting in exciting advancements in pluripotent stem cell differentiation, tissue bioengineering, and the potential for developing novel regenerative therapies for kidney disease. Lineage tracing, or the labeling of progeny cells arising from a single cell or group of cells, allows for spatial and temporal analyses of dynamic in vivo and in vitro processes. As lineage tracing techniques expand across disciplines of developmental biology, stem cell biology, and regenerative medicine, careful experimental design and interpretation, along with an understanding of the basic principles and technical limitations, are essential for utilizing genetically complex lineage tracing models to further understand kidney development and disease.