Phosphodiesterase 11A (PDE11A) Expression in Mouse Tissues and Characterization of a PDE11A Mouse Knock-Out Model

Abstract

Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides and maintain physiologic levels of intracellular concentrations of cAMP and cGMP. Increased cAMP signaling has been associated with genetics disorders that lead to adrenocortical tumors and Cushing syndrome. Genetics defects in the phosphodiesterase 11A (PDE11A) are associated with increased levels of cAMP and bilateral adrenal hyperplasia; they also contribute to the development of adrenocortical, prostate, and testicular tumors in the general population. The aim of the present work is to study the expression of Pde11a in mouse tissues, as well as to understand better the Pde11a defect in a previously published Pde11a–/– knockout (KO) mouse model.1A colony of Pde11a–/– (KO), Pde11a+/– (Het) and wild type (wt) mice was studied in a complete phenotypical groß and microscopy pathological study. Molecular, immunohistochemical and biochemical studies were done to determine the function and expression of Pde11a in the tissues of normal and mutant mice. In normal mice higher PDE11A immunoreactivity(PDE11A-IR) was found in small intestine villi, thyroid follicular cells, prostate and spermatocytes; moderate PDE11A-IR in brain, liver hepatocytes, and exocrine pancreas and little, if any, in the pituitary gland. In mutant mice RNA studies showed a reduced Pde11a expression in steroidogenic tissues (adrenals and testis), lung, brain, and liver while prostate and kidney presented comparable expression with normal mice. PDE11A protein expression and activity assays did not show differences among three groups. Pathological studies showed differences: Adrenal subcapsular hyperplasia and foamy cells were more frequent in Het(37.7% and 30.2% respectively, p<0.05) than in wt group (26.3% and 15.8% respectively); Spinal epidermoid cyst in Het (15%) and wt mice (10%); kidney-pelvis interstitial lymphocytes only in KO mice (10.7%, P<0.05). KO mice showed increased absolute and organ specific weight. This study show a clear profile of Pde11a protein expression in endocrine and other mouse tissues, as well as convincing evidence of only partial Pde11a suppression in the previously published KO mouse. These mice developed adrenal hyperplasia and other abnormalities like humans with heterozygote PDE11A defects and partial inactivation of the enzyme. These data support the involvement of PDE11A in the pathogenesis of adrenocortical hyperplasia, but also provide significant insight into a previously reported mouse model.