The Glucocorticoid-Induced Leucine Zipper (Gilz/Tsc22d3-2) Gene Locus Plays a Crucial Role in Male Fertility

Abstract

The glucocorticoid-induced leucine zipper (Tsc22d3-2) is a widely expressed dexamethasone-induced transcript that has been proposed to be important in immunity, adipogenesis, and renal sodium handling based on in vitro studies. To address its function in vivo, we have used Cre/loxP technology to generate mice deficient for Tsc22d3-2. Male knockout mice were viable but surprisingly did not show any major deficiencies in immunological processes or inflammatory responses. Tsc22d3-2 knockout mice adapted to a sodium-deprived diet and to water deprivation conditions but developed a subtle deficiency in renal sodium and water handling. Moreover, the affected animals developed a mild metabolic phenotype evident by a reduction in weight from 6 months of age, mild hyperinsulinemia, and resistance to a high-fat diet. Tsc22d3-2-deficient males were infertile and exhibited severe testis dysplasia from postnatal d 10 onward with increases in apoptotic cells within seminiferous tubules, an increased number of Leydig cells, and significantly elevated FSH and testosterone levels. Thus, our analysis of the Tsc22d3-2-deficient mice demonstrated a previously uncharacterized function of glucocorticoid-induced leucine zipper protein in testis development.

Glucocorticoid-Induced Leucine Zipper Enhanced Expression in Dendritic Cells Is Sufficient To Drive Regulatory T Cells Expansion In Vivo

“…This would explain why we did not detect a global phenotype alteration in DCs from GILZ hi DCs in vitro under steady-state or after TLR engagement, results that corroborate the data obtained by other groups using GILZknockout mice (43,44). GILZ is known to inhibit transcription factors like NF-kB, AP1, and FoxO3 (12).…”

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…These proteins likely work in concert with the ubiquitin ligase Nedd4-2 that is involved in the endocytic pathway. No evidence supports a limiting role of these proteins for the aldosterone effect on ENaC, because mouse models with complete knockout of the genes encoding these proteins (Nedd4-2, SGK, USP2-45, GILZ) failed to suppress the response of ENaC-mediated renal Na + absorption to aldosterone (Fejes-Toth et al, 2008;Suarez et al, 2012;Pouly et al, 2013;Ronzaud et al, 2013). The complete picture of the aldosterone signaling pathway that controls ENaCmediated Na + absorption remains therefore largely unknown.…”

Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells1

“…TSC22D3 (GILZ, glucocorticoid-induced leucine zipper) is a member of the TSC22-domain leucine zipper family. Despite being present in several cell types and tissues, including the kidney, brain, lung, heart, thymus, liver, and testis, the role of TSC22D3 remains to be fully defined [28]. Interestingly, male knockout mice for Tsc22d3 are infertile due to lower size and weight of the testes, absence of germ cells, and increased apoptosis in the seminiferous tubules [28,29].…”