Project description:This project is designed to measure changes in gene expression during sea lamprey development RNA was extracted from sea lamprey embryos at 1, 2, 2.5, 3, 4, and 5 days post-fertilization and used to generate RNAseq data
Project description:Haploinsufficiency of the progranulin (PGRN) protein is a leading cause of frontotemporal lobar degeneration (FTLD). Mouse models have been developed to study PGRN functions. However, PGRN deficiency in the commonly used C56BL/6 mouse strain background leads to very mild phenotypes, and pathways regulating PGRN deficiency phenotypes remain to be elucidated. We generated PGRN-deficient mice in the FVB/N background and compared PGRN deficiency phenotypes between C56BL/6 and FVB/N background via immunostaining, western blot, RNA-seq, and proteomics approaches. We also identified sPLA2-IIA as a novel binding partner of PGRN and demonstrated the importance of sPLA2-IIA in modifying PGRN deficiency phenotypes using inhibitor treatment and AAV-mediated overexpression in mouse models. We report that PGRN loss in the FVB/N mouse strain results in earlier onset and stronger FTLD-related and lysosome-related phenotypes. We found that PGRN interacts with sPLA2-IIA, a member of the secreted phospholipase A2 (sPLA2) family member and a key regulator of inflammation that is expressed in FVB/N but not C56BL/6 background. sPLA2-IIA inhibition rescues PGRN deficiency phenotypes and sPLA2-IIA overexpression drives enhanced gliosis and lipofuscin accumulation in PGRN-deficient mice. Additionally, RNA-seq and proteomics analysis revealed that mitochondrial pathways are upregulated in the PGRN-deficient C57BL/6 mice but not in the FVB/N mice. Our studies establish a better mouse model for FTLD-GRN and uncover novel pathways modifying PGRN deficiency phenotypes.
Project description:Regulation of embryonic liver growth remains largely elusive. Progranulin has been discussed in pathological liver growth; however, the functional role of Pgrn in embryonic liver growth has never been addressed. Knockdown of GrnA, the orthologue of mammalian pgrn in zebrafish, displayed a deficient hepatic outgrowth during hepatogenesis. Expression profiles manifested that pgrn-deficiency impaired hepatogenesis associated with dysregulation of Met signaling. Pgrn regulates hepatic expression of Met was further verified in vitro and in vivo. These results indicate that Pgrn is a novel factor required for embryonic hepatic outgrowth and reveal a novel link between Pgrn and Met signaling. To explore the GrnA induced genomic responses during hepatic outgrowth, mRNA expression profiles were compared from grnA morphants and control embryos using zebrafish 14K oligonucleotide microarray at 72 hpf, when hepatocytes were rapid proliferating.
Project description:The identification of homologous cell types across species represents a crucial step in understanding cell type evolution. The retina is particularly amenable to comparative analysis because the basic morphology, connectivity, and function of its six major cell classes have remained largely invariant since the earliest stages of vertebrate evolution. We used comparative single-nucleus chromatin accessibility analysis of lamprey, fish, bird, and mammalian retinas, which began to diverge over half a billion years ago, to demonstrate cross-species conservation of cis-regulatory codes in all six retinal cell classes. In this study, we acquired retinal single-cell gene expression profiling (scRNA-seq) and single-nucleus chromatin accessibility (snATAC-seq) from sea lamprey (Petromyzon marinus), a jawless species. We also acquired long-read sequence data from lamprey retina and single-nucleus chromatin accessibility from chicken (Gallus gallus).
Project description:The identification of homologous cell types across species represents a crucial step in understanding cell type evolution. The retina is particularly amenable to comparative analysis because the basic morphology, connectivity, and function of its six major cell classes have remained largely invariant since the earliest stages of vertebrate evolution. We used comparative single-nucleus chromatin accessibility analysis of lamprey, fish, bird, and mammalian retinas, which began to diverge over half a billion years ago, to demonstrate cross-species conservation of cis-regulatory codes in all six retinal cell classes. In this study, we acquired retinal single-cell gene expression profiling (scRNA-seq) and single-nucleus chromatin accessibility (snATAC-seq) from sea lamprey (Petromyzon marinus), a jawless species. We also acquired long-read sequence data from lamprey retina and single-nucleus chromatin accessibility from chicken (Gallus gallus).
Project description:The identification of homologous cell types across species represents a crucial step in understanding cell type evolution. The retina is particularly amenable to comparative analysis because the basic morphology, connectivity, and function of its six major cell classes have remained largely invariant since the earliest stages of vertebrate evolution. We used comparative single-nucleus chromatin accessibility analysis of lamprey, fish, bird, and mammalian retinas, which began to diverge over half a billion years ago, to demonstrate cross-species conservation of cis-regulatory codes in all six retinal cell classes. In this study, we acquired retinal single-cell gene expression profiling (scRNA-seq) and single-nucleus chromatin accessibility (snATAC-seq) from sea lamprey (Petromyzon marinus), a jawless species. We also acquired long-read sequence data from lamprey retina and single-nucleus chromatin accessibility from chicken (Gallus gallus).
Project description:Regulation of embryonic liver growth remains largely elusive. Progranulin has been discussed in pathological liver growth; however, the functional role of Pgrn in embryonic liver growth has never been addressed. Knockdown of GrnA, the orthologue of mammalian pgrn in zebrafish, displayed a deficient hepatic outgrowth during hepatogenesis. Expression profiles manifested that pgrn-deficiency impaired hepatogenesis associated with dysregulation of Met signaling. Pgrn regulates hepatic expression of Met was further verified in vitro and in vivo. These results indicate that Pgrn is a novel factor required for embryonic hepatic outgrowth and reveal a novel link between Pgrn and Met signaling.
Project description:Progranulin (PGRN) is a lysosomal protein involved in various neurodegenerative diseases. Over 70 mutations discovered in the GRN gene all result in reduced expression of PGRN protein. However, the detailed molecular function of PGRN within lysosomes and the impact of PGRN deficiency on lysosomal biology remain unclear. Here we leveraged multi-faceted proteomic techniques to comprehensively characterize how PGRN deficiency changes the molecular and functional landscape of neuronal lysosomes.