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cAMP and cGMP are intracellular signaling molecules produced in response to a plethora of extracellular signals in order to coordinate cellular metabolism, proliferation, differentiation and apoptosis. Phosphodiesterases (PDEs) are the enzymes that hydrolyze cAMP and cGMP in order to end or to limit the responses to these signals.
To date 11 PDE families (named PDE1 to PDE11) have been identified across each cell type expressed in a peculiar pattern. They enclose 21 genes that codify approximately 100 enzymes that form a redundant network ensuring the compensation of activity in case of alteration of activity or lack of expression of one of the members. PDE2A, a cAMP-hydrolyzing enzyme, represents the exception to this picture, as PDE2A knockout is embryonic lethal. Knockout embryos show that the lack of the enzyme has the greatest impact on the development of the heart and of the liver, which is no longer able to assume its hematopoietic role. The increase of the intracellular cAMP level and the downregulation of the anti-apoptotic gene Bcl2 might explain the loss of integrity in the PDE2A knockout liver niche that compromises the hematopoietic function and maturation.
1. Introduction
During most of prenatal development, the fetal liver (FL) provides the specific niche required for hematopoiesis. Its components, hepatoblasts, resident macrophages, fibroblasts, vascular smooth muscle, stromal and endothelial cells participate with extracellular matrix (ECM) and humoral factors to its generation [1]. In the mouse, 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].
A plethora of genetic alterations affecting liver development has been reported to compromise hematopoiesis. By examining in vitro proliferation and differentiation of the hematopoietic committed progenitors it is possible to distinguish if defects are being housed in the niche or in the hematopoietic precursors themselves [4][5][6]. Phosphodiesterases (PDEs) are essential components of cellular signaling that regulate the response to several stimuli (hormones, neurotransmitters) by modulating intracellular levels of cyclic nucleotides [7]. PDEs are expressed in different combinations in tissues and in cellular compartments allowing the proper regulation of cyclic nucleotides signaling [8]. Some PDEs are cAMP or cGMP-specific or, as in the case of phosphodiesterase 2A (PDE2A), they can hydrolyze both cAMP and cGMP. In the adult mouse, PDE2A has a widespread tissue distribution but brain, heart, liver and adrenal gland show the greatest level of expression. Mouse development is compromised in PDE2A knockout embryos [9]. PDE2A deficiency causes cardiac defects, associated to the increase of cAMP level and of ICER, a cAMP-dependent transcriptional repressor, which in turn reduces the expression of genes essential for cardiomyocyte differentiation [10]. The role of PDE2A in liver development and hematopoiesis has been not yet established, but in the adult the role of cyclic nucleotides in regulating protein kinase activity and gene transcription for key liver functions is well documented [11][12].
Here we report a new role of PDE2A in FL. The absence of this enzyme severely affects the development of this organ at the structural, cellular and molecular levels with severe consequences on its role in prenatal hematopoiesis.
2. Results
PDE2A knockout embryos die at E15.5 with evident cardiac and hepatic defects (FIGURE 1). At the time of death, their liver weighs only 25% of the wild type counterpart. At a microscopical level such livers display loss of the normal structure: the cells are less densely packed, the central vein in the lobule is absent and the erythroblasts, easily detected at E14.5 in normal livers are scarcely represented. The manifestation of such phenotype is probably due to the increase in intracellular cAMP concentration that in PDE2A−/− livers is significantly higher compared to the levels detected in the liver of PDE2A+/+ embryos. The high cAMP level can deregulate the cellular pathways it controls. As a matter of fact, overall, the results suggest that in vivo PDE2A contributes to hepatoblast, stromal and endothelial cells differentiation/survival.
In particular, in PDE2A−/− embryos:
-Liver hypoplasia is caused by apoptotic increase rather than decrease of cellular proliferation. Hence, the PDE2A/cAMP signaling may play a role in protecting liver cells from apoptotic factors during development.
-The absence of PDE2A induces apoptosis of different cell types that contribute to the liver niche and this in turn affects the differentiation of hematopoietic stem cells that have colonized fetal liver of PDE2A−/−.