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.
Highlights
During most of prenatal development, the fetal liver (FL) provides the specific niche required for hematopoiesis
We show for the first time the gross aberrations in Phosphodiesterase 2A (PDE2A)−/− fetal liver and hematopoiesis, indicating that PDE2A is primarily required for liver development and secondarily for hematopoietic development
We show that the lack of PDE2A results in profound defects in early liver development
Summary
During most of prenatal development, the fetal liver (FL) provides the specific niche required for hematopoiesis. At embryonic day 11.5 (E11.5), hematopoietic stem cells (HSC), after their formation in the yolk sac, aorta-gonad-mesonephros region, and placenta, migrate in FL attracted by chemical signals. In FL between E12 and E16, HSC dramatically increase in number and differentiate into mature hematopoietic cells, which are necessary to sustain the ongoing growth of the embryo [2]. Around E16, the hematopoietic function of FL starts to decline in favor of the bone marrow and the liver begins to acquire specific metabolic functions, which include carbohydrate and lipid metabolism [3]. Phosphodiesterases (PDEs) are essential components of cellular signaling that regulate the response to several stimuli (hormones, neurotransmitters) by modulating intracellular levels of cyclic nucleotides. There are eleven mammalian PDEs families encoded by numerous genes and each of them can give rise to several splicing variants [7]
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