Antizyme Inhibitor 2 Hypomorphic Mice. New Patterns of Expression in Pancreas and Adrenal Glands Suggest a Role in Secretory Processes

Abstract

The intracellular levels of polyamines, polycations implicated in proliferation, differentiation and cell survival, are regulated by controlling their biosynthesis, catabolism and transport. Antizymes and antizyme inhibitors are key regulatory proteins of polyamine levels by affecting ornithine decarboxylase, the rate-limiting biosynthetic enzyme, and polyamine uptake. We recently described the molecular function of a novel antizyme inhibitor (AZIN2). However, the physiological function of AZIN2 in mammals is mostly unknown. To gain insight on the tissue expression profile of AZIN2 and to find its possible physiological role, we have generated, transgenic mice with severe Azin2 hypomorphism. This mouse model expresses transgenic bacterial β-D-galactosidase as a reporter gene, under the control of the Azin2 endogenous promoter, what allows a very sensitive and specific detection of the expression of the gene in the different tissues of transgenic mice. The biochemical and histochemical analyses of β-D-galactosidase together with the quantification of Azin2 mRNA levels, corroborated that AZIN2 is mainly expressed in testis and brain, and showed for the first time that AZIN2 is also expressed in the adrenal glands and pancreas. In these tissues, AZIN2 was not expressed in all type of cells, but rather in specific type of cells. Thus, AZIN2 was mainly found in the haploid germinal cells of the testis and in different brain regions such as hippocampus and cerebellum, particularly in specific type of neurons. In the adrenal glands and pancreas, the expression was restricted to the adrenal medulla and to the Langerhans islets, respectively. Interestingly, plasma insulin levels were significantly reduced in the transgenic mice. These results support the idea that AZIN2 may have a role in the modulation of reproductory and secretory functions and that this mouse model might be an interesting tool for the progress of our understanding on the role of AZIN2 and polyamines in specific mammalian cells.

A radial histogenetic model of the mouse pallial amygdala

“…Our molecular description is based on adult AZIN2-LacZ labelling, combined with a glimpse at Lhx9 and Er81 expression (Nery et al 2002;Remedios et al 2004;Tole et al 2005;Garcia-Lopez et al 2008;Abellán et al 2009;Tosches et al 2018). The AZIN2 gene (ornithine-decarboxylase antizyme inhibitor 2) codes a non-functional ornithine-decarboxylase paralog protein, which blocks specific antizymes (AZ1-3), thus increasing polyamine synthesis and function (López-Garcia et al 2013). It is heterogeneously present in the adult mouse brain (Martínez-de-la-Torre et al 2018;Puelles et al 2019), and throws new light upon adult amygdalar radial structure.…”

An exercise in brain genoarchitectonics: Analysis of AZIN2‐Lacz expressing neuronal populations in the mouse hindbrain

“…In contrast, ODC appears in the cytoplasm, and AZIN1 is found in the cell nucleus (Lopez‐Contreras et al ). AZIN2 is expressed mostly in the testis and the brain (López‐Contreras et al, ; López‐García et al, ). The role of AZIN2 in the adult brain, where it is characterized by a discontinuous distribution (expressed selectively in a variety of cell populations, but not in all neurons), is far from understood.…”

“…In vivo studies with mutant mice where the gene‐trap technique disrupted the AZIN1 gene indicated that AZIN1 is essential for the survival of mice; the affected mice exhibited perturbed levels of ODC, putrescine, and spermidine (Tang et al ). Mice with AZIN2 ablation are viable (López‐García et al, ) and similar studies will be required to determine the role of AZIN2 in the adult brain, examining whether this protein is also involved in perinatal brain development or functions.…”

“…The present investigation describes in detail the expression pattern of AZIN2 in the adult mouse hindbrain, using a transgenic mouse line in which beta‐galactosidase (LacZ) expression was linked to the AZIN2 gene promoter (López‐García et al, ).…”

Expression of ODC Antizyme Inhibitor 2 (AZIN2) in Human Secretory Cells and Tissues

“…Lopez-Garcia et al created AZIN2 hypomorphic mice and found evidence for regulatory influence of AZIN2 on secretion of insulin from pancreatic islets [ 22 ].…”