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Progranulin A mediated MET signalling is essential for liver morphogenesis in zebrafish

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE19211 | GEO | 2010/11/10

SECONDARY ACCESSION(S): PRJNA120825

REPOSITORIES: GEO

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Progranulin A mediated MET signalling is essential for liver morphogenesis in zebrafish

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.

2010-11-10 | E-GEOD-19211 | biostudies-arrayexpress

Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.

Project description:Multiple FTD patient-specific iPSC lines were generated for the first time, Human neurons of progranulin haploinsufficiency have been established. PGRN S116X neurons are more sensitive to kinase inhibitors-induced cell stress, which can be rescued by ectopic progranulin expression, revealing progranulin-dependent cellular defects in FTD. Microarray analysis reveals that the serine/threonine kinase S6K2 (RPS6KB2) and other genes involved in MAPK signaling are dysregulated specifically in neurons with progranulin deficiency. 32 independent human neuronal cultures were analyzed in this study

2012-10-25 | E-GEOD-40378 | biostudies-arrayexpress

Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects.

2012-10-25 | GSE40378 | GEO

Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy

Project description:Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.

2024-01-18 | GSE180672 | GEO

Restoration of Progranulin Expression Rescues Cortical Neuron Generation in Induced Pluripotent Stem Cell Model of Frontotemporal Dementia

Project description:To understand how haploinsufficiency of progranulin (PGRN) protein causes frontotemporal dementia (FTD), we created induced pluripotent stem cells (iPSC) from patients carrying the GRNIVS1+5G>C mutation (FTD-iPSCs). FTD-iPSCs were fated to cortical neurons, the cells most affected in FTD and known to express PGRN. Although generation of neuroprogenitors was unaffected, their further differentiation into neurons, especially CTIP2-, FOXP2- or TBR1-TUJ1 double positive cortical neurons, was significantly decreased in FTD-neural progeny. Zinc finger nuclease-mediated introduction of PGRN cDNA into the AAVS1 locus corrected defects in cortical neurogenesis, demonstrating that PGRN haploinsufficiency causes inefficient cortical neuron generation. RNAseq analysis confirmed reversal of altered gene expression profile following genetic correction. Wnt signaling pathway, one of the top defective pathways in FTD-iPSC-derived neurons coupled with its reversal following genetic correction, makes it an important candidate. Therefore, we demonstrate for the first time that PGRN haploinsufficiency hampers corticogenesis in vitro.

2014-11-12 | GSE60902 | GEO

Rescue of TDP-43 and neuronal pathologies by peripheral AAV-mediated expression of brain-penetrant progranulin in a mouse model of GRN-linked frontotemporal lobar degeneration

Project description:Progranulin (PGRN) haploinsufficiency is a major risk factor for Frontotemporal Lobar Degeneration with TDP-43 pathology (FTLD-TDP). Protein replacement therapeutic strategies are currently in clinical development, intended to restore PGRN levels in the central nervous system and slow or halt disease progression. However, such approaches require repeated dosing. Here, we explored the use of adeno-associated virus (AAV) to achieve sustained expression of a brain penetrant PGRN fusion protein, composed of a single chain variable fragment (scFv) recognizing mouse transferrin receptor (TfR) fused to human PGRN (AAV(L):bPGRN). We evaluated this approach for its ability to rescue pathological phenotypes in a double knockout mouse model lacking both PGRN and TMEM106b. A single administration of AAV(L):bPGRN reduced FTLD-TDP associated pathologies including severe motor function deficits, formation of insoluble, abnormally processed and phosphorylated TDP-43, as well as dysfunctional protein degradation, lipid dysregulation and gliosis.

2023-07-16 | GSE235515 | GEO

Multi-modal Proteomic Characterization of Lysosomal Function and Proteostasis in Progranulin-Deficient Neurons

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.

2023-02-18 | MSV000091322 | MassIVE

Protein expression in the prefrontal cortex of aged mice with progranulin deficiency or neuronal progranulin overexpression

Project description:Description: Progranulin deficiency is associated with neurodegeneration in humans and in mice. We performed a deep proteomic screen of the pre-frontal cortex in aged (13-15 months) female progranulin-deficient mice (GRN-/-) and mice with a neuron-specific inducible overexpression of progranulin (SLICK-GRN-OE with tamoxifen) versus the respective control mice (Grn+/+ and SLICK-Grn without Tamoxifen). The data set shows progranulin-dependent alterations of protein expression in the cortex of mice.

2016-10-13 | PXD004087 | Pride

Longitudinal characterization of transcriptomic, functional, and morphological features in human iPSC-derived neurons and their application to investigate translational progranulin disease biology

Project description:The disease biology of frontotemporal lobe dementia (FTD) is complex and not fully understood, with limited translational value appreciated from animal models to date. Human cellular systems that can recapitulate phenotypic features of disease offer promise as translational tools to not only increase our understanding of disease processes but also increase the probability of success of translating novel treatment options to patients. However not all researchers may necessarily have access to well characterized induced pluripotent stem cell (iPSC)-derived human neurons. We therefore sought to comprehensively profile phenotypic features over time in one commercially-available IPSC-derived human neuron cell line. This included systems-level assessments of neurite outgrowth dynamics, neuronal network function and genome-wide gene expression. By investigating progranulin biology as an example we then demonstrated utility of these cells as a tool to investigate human disease biology. For example, by using siRNA-mediated knockdown of the progranulin (GRN) gene, we demonstrated establishment of an isogenic human cellular model to facilitate translational FTD research. We reproduced findings from rodent neurons by demonstrating that recombinant progranulin (rPGRN) mediated neuroprotection. Contrary to previous rodent data, in our human cellular models, growth factor treatment showed no consistent sensitivity to modulate neurite outgrowth dynamics. Our study further provides first evidence that rRPGRN modulated neuronal firing and synchrony in human neurons. Taken together, our datasets are a valuable systems-level resource demonstrating the utility of the tested commercially-available human iPSC neurons for investigating basic human neurobiology, translational neuroscience, and drug discovery applications in neurodegenerative and other CNS diseases.

2020-09-07 | GSE157573 | GEO

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin deficient mice [neuroinflammation panel]

Project description:Polygenic risk factors influence onset and progression of neurodegenerative diseases, but are difficult to be functionally explored in isolation. Single nucleotide polymorphisms (SNPs) in TMEM106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN mutation carriers. Currently, it is not clear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss-of-function of TMEM106B is responsible for the increased disease risk of patients with PGRN haploinsufficiency. We therefore compared behavioral abnormalities, gene expression patterns, lysosomal activity and TDP-43 pathology in single and double knockout animals. Grn–/–/Tmem106b–/– mice showed a strongly reduced life span and massive motor deficits. Gene expression analysis revealed an upregulation of molecular signatures characteristic for disease associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as a pronounced accumulation of ubiquitinated proteins and wide spread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn–/– knockouts only occasionally showed TDP-43 pathology, the double knockout mice exhibit robust deposition of phosphorylated TDP-43. Thus, a loss-of-function of TMEM106B may enhance the risk for GRN-associated FTD by reduced protein turnover in the lysosomal/autophagic system.

2020-07-25 | GSE155066 | GEO

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