A critical role for NF2 and the Hippo pathway in branching morphogenesis
نویسندگان
چکیده
Branching morphogenesis is a complex biological process common to the development of most epithelial organs. Here we demonstrate that NF2, LATS1/2 and YAP play a critical role in branching morphogenesis in the mouse kidney. Removal of Nf2 or Lats1/2 from the ureteric bud (UB) lineage causes loss of branching morphogenesis that is rescued by loss of one copy of Yap and Taz, and phenocopied by YAP overexpression. Mosaic analysis demonstrates that cells with high YAP expression have reduced contribution to UB tips, similar to Ret(-/-) cells, and that YAP suppresses RET signalling and tip identity. Conversely, Yap/Taz UB-deletion leads to cyst-like branching and expansion of UB tip markers, suggesting a shift towards tip cell identity. Based on these data we propose that NF2 and the Hippo pathway locally repress YAP/TAZ activity in the UB to promote subsequent splitting of the tip to allow branching morphogenesis.
منابع مشابه
Investigating the mRNA expression levels of Hippo pathway in adenoma polyps
Background Neoplastic adenomatous polyps generating from the epithelial cells are considered benign tumors. Adenomatous polyps are common in western countries and it can take seven to 10 or more years for an adenoma to evolve into cancer. The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the r...
متن کاملYAP is essential for mechanical force production and epithelial cell proliferation during lung branching morphogenesis
Branching morphogenesis is a fundamental program for tissue patterning. We show that active YAP, a key mediator of Hippo signaling, is distributed throughout the murine lung epithelium and loss of epithelial YAP severely disrupts branching. Failure to branch is restricted to regions where YAP activity is removed. This suggests that YAP controls local epithelial cell properties. In support of th...
متن کاملThe Hippo Pathway Member Nf2 Is Required for Inner Cell Mass Specification
During mammalian development, the first two lineages to be specified are the trophectoderm (TE) and the inner cell mass (ICM). The Hippo pathway kinases Lats 1 and 2 (Lats1/2) and the transcriptional coactivator Yap play important roles in this specification process [1]. In outside cells of the embryo, Yap is nuclear localized and cooperates with Tead4 to induce the TE-specifying transcription ...
متن کاملHow Hippo Signaling Pathway Modulates Cardiovascular Development and Diseases
Cardiovascular disease remains the leading cause of death around the globe. Cardiac deterioration is associated with irreversible cardiomyocyte loss. Understanding how the cardiovascular system develops and the pathological processes of cardiac disease will contribute to finding novel and preventive therapeutic methods. The canonical Hippo tumor suppressor pathway in mammalian cells is primaril...
متن کاملSpatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2
Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning t...
متن کامل