Project description:Activated hepatic stellate cells orchestrate scar formation during fibrotic liver injury. Recent evidence has shown limited quiescent precursor derivation from the mesoderm during development. Here, we use lineage-tracing from development, through adult homeostasis, to adult fibrotic injury, to show that discreet subpopulations of activated hepatic stellate cells are defined by expression of WT1, a transcription factor controlling morphological transitions in organogenesis and adult homeostasis. Morphologically and transcriptionally distinct subpopulations are evident in fibrotic human disease and animal models. Populations defined by WT1 expression after injury derive from a discreet population of quiescent adult precursors originating from the embryonic mesothelium. WT1-deletion permits morphological transition to an enhanced fibrotic myofibroblast phenotype. Our findings demonstrate functional heterogeneity of adult scar-forming cells that can be whole-life traced back through specific quiescent precursors in adult homeostasis to differential origin in development, and defines WT1 as a paradoxical anti-fibrotic regulator during adult injury.
Project description:Sex differences in liver gene expression are dictated by sex-differences in circulating growth hormone (GH) profiles. Presently, the pituitary hormone dependence of mouse liver gene expression was investigated on a global scale to discover sex-specific early GH response genes that might contribute to sex-specific regulation of downstream GH targets and to ascertain whether intrinsic sex-differences characterize hepatic responses to plasma GH stimulation. RNA expression analysis using 41,000-feature microarrays revealed two distinct classes of sex-specific mouse liver genes: genes subject to positive regulation (class-I) and genes subject to negative regulation by pituitary hormones (class-II). Genes activated or repressed in hypophysectomized (Hypox) mouse liver within 30-90min of GH pulse treatment at a physiological dose were identified as direct targets of GH action (early response genes). Intrinsic sex-differences in the GH responsiveness of a subset of these early response genes were observed. Notably, 45 male-specific genes, including five encoding transcriptional regulators that may mediate downstream sex-specific transcriptional responses, were rapidly induced by GH (within 30min) in Hypox male but not Hypox female mouse liver. The early GH response genes were enriched in 29 male-specific targets of the transcription factor Mef2, whose activation in hepatic stellate cells is associated with liver fibrosis leading to hepatocellular carcinoma, a male-predominant disease. Thus, the rapid activation by GH pulses of certain sex-specific genes is modulated by intrinsic sex-specific factors, which may be associated with prior hormone exposure (epigenetic mechanisms) or genetic factors that are pituitary-independent, and could contribute to sex-differences in predisposition to liver cancer or other hepatic pathophysiologies.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility. Gene expression was measured in whole testis from males aged 62-86 days. Samples include 190 first generation lab-bred male offspring of wild-caught mice from the Mus musculus musculus - M. m. domesticus hybrid zone.
