Dataset Information

PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis.

ABSTRACT: Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A^-/-) is embryonic lethal. Notably, livers of PDE2A^-/- embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular analyses revealed loss of integrity in the PDE2A^-/- liver niche that compromises the hematopoietic function and maturation. Hematopoietic cells isolated from PDE2A^-/- livers are instead able to differentiate in in vitro assays, suggesting the absence of blood cell-autonomous defects. Apoptosis was revealed in hepatoblasts and at the endothelial and stromal compartments in livers of PDE2A^-/- embryos. The increase of the intracellular cAMP level and of the inducible cAMP early repressor (ICER) in liver of PDE2A^-/- embryos might explain the impairment of liver development by downregulating the expression of the anti-apoptotic gene Bcl2. In summary, we propose PDE2A as an essential gene for integrity maintenance of liver niche and the accomplishment of hematopoiesis.

SUBMITTER: Barbagallo F

PROVIDER: S-EPMC7215450 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis.

Barbagallo Federica F Rotilio Valentina V Assenza Maria Rita MR Aguanno Salvatore S Orsini Tiziana T Putti Sabrina S Isidori Andrea M AM Lenzi Andrea A Naro Fabio F De Angelis Luciana L Pellegrini Manuela M

International journal of molecular sciences 20200421 8

Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A-/-) is embryonic lethal. Notably, livers of PDE2A-/- embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular analyses revealed loss of integrity in the PDE2A-/- liver niche that compromises the hematopoietic function and maturation. Hematopoietic cells isolat ...[more]

PMID: 32326334

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Project description:Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/−) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/− mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. To obtain a more comprehensive understanding of the changes within HSPCs at the molecular level, we employed single-cell RNA-sequencing (scRNAseq) using both WT and Son+/− bone marrow HSPCs isolated and sorted based on their Lin− cKit+ (LK) cell markers (24,355 total LK cells from 2 WT mice; 31,232 total LK cells from 2 Son+/− mice. The linage-marker-negative (Lin-) c-kit+ population containing hematopoietic stem and progenitor cells was sorted from dissociated mouse bone marrow cells by flow cytometry. Sorted single-cell suspension, 10x barcoded gel beads and oil (10xGenomics Chromium Next GEM Single Cell 3' Kit v3.1 PN 1000268) were loaded into 10x Chromium™ Single Cell Chip to capture single cells into nanoliter-scale oil droplets by 10xChromium X Controller and generate Gel Bead-In-EMulsions (GEMs). cDNA from single cells were synthesized and barcoded by incubation of the GEMs in a thermocycler machine and then purified from GEMs by DynaBeads (10xGenomics PN 2000048). cDNA was pre-amplified by PCR to generate sufficient mass for sequencing library construction. The single-cell cDNA libraries were constructed by following 10xGenomics 3’ NextGem 3.1 version kit instructions. The final constructed 3’-biased single-cell libraries were sequenced by the Illumina Novaseq6000 machine, targeting 50,000 read pairs/cell. We identified hematopoietic abnormalities in Son+/− mice, including leukocytopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency inclines cell fate toward the myeloid lineage but compromises lymphoid lineage development by reducing genes required for lymphoid and B-cell lineage specification. Additionally, Son haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythroid maturation. These findings highlight the importance of the full gene dosage of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

Dataset Information

PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis.

Publications

PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis.

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