Project description:In order to investigate how NICD2 promotes cyst growth, we carried out bulk RNA-Seq analysis of kidneys from PKD mouse models R26NICD2/+KspCre.
Project description:In order to investigate how NICD2 promotes cyst growth, we carried out bulk RNA-Seq analysis of kidneys from PKD mouse model R26NICD2/+ Pax8-rtTA mice.
Project description:While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid-induced nephropathy, unilateral ureteral obstruction, or APOL1-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline, but showed protection from folic acid induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knock-out of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Kidney tubule specific deletion of Tfam resulted in fibrosis. In summary, Jag1/Notch2 plays a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.
Project description:We applied unbiased cell type specific transcriptional profiling by translating ribosome affinity purification (TRAP) to mouse kidneys with polycystin-1 and cilia inactivation at a stage prior kidney tubule cyst formation. We identified differentially expressed actively translating mRNA that correlated with the cilia dependent cyst activation (CDCA) pattern common to male and female mice. This differential translatome offers opportunities for mechanistic discovery in polycystin and cilia related kidney phenotypes.
Project description:During kidney development, Notch signaling plays multiple roles including promoting differentiation of nephron progenitors that give rise to all of the epithelial cells found in the nephron. Little is known about what genes Notch signaling regulates and how Notch signaling interacts with other transcription factors. To address this, we carried out genome-wide mapping of Notch2, a major Notch receptor required for differentiation of nephron progenitors, in the embryonic kidney.