FBXO38 Ubiquitin Ligase Controls Sertoli Cell Maturation

Nikol Dibus; Eliska Zobalova; Mario A M Monleon; Vladimir Korinek; Dominik Filipp; Jana Petrusova; Radislav Sedlacek; Petr Kasparek; Lukas Cermak

doi:10.3389/fcell.2022.914053

FBXO38 Ubiquitin Ligase Controls Sertoli Cell Maturation

Front Cell Dev Biol. 2022 Jun 13:10:914053. doi: 10.3389/fcell.2022.914053. eCollection 2022.

Authors

Nikol Dibus^{1

2}, Eliska Zobalova¹, Mario A M Monleon¹, Vladimir Korinek³, Dominik Filipp⁴, Jana Petrusova⁴, Radislav Sedlacek⁵, Petr Kasparek⁵, Lukas Cermak¹

Affiliations

¹ Laboratory of Cancer Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czechia.
² Faculty of Science, Charles University, Prague, Czechia.
³ Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia.
⁴ Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia.
⁵ Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czechia.

Abstract

The ubiquitin ligase SCF^FBXO38 controls centromeric chromatin by promoting the degradation of the ZXDB protein. To determine the importance of this pathway during development, Fbxo38-deficient mice were generated. The loss of FBXO38 resulted in growth retardation affecting several organs, including the male reproductive system. A detailed analysis of the mutant testes revealed pathological changes in the seminiferous tubules, accompanied by a significant decrease in sperm production and reduced fertility. In adult testes, FBXO38 was specifically expressed in Sertoli cells, a somatic population essential for spermatogenesis initiation and progression. Sertoli cells lacking FBXO38 exhibited stabilized ZXDB protein and upregulated centromeric chromatin. Furthermore, the gene expression profile revealed that the absence of FBXO38 led to a defect in Sertoli cell maturation, specifically characterized by dysregulation in genes controlling retinoic acid metabolism and intercellular communication. Consequently, we documented significant changes in their ability to initiate spermatogonial differentiation. In conclusion, we show that FBXO38 acts as a Sertoli cell maturation factor, affecting the Sertoli cell transcription program, centromere integrity, and, subsequently, the ability to control spermatogenesis.

Keywords: centromere; proteasome; retinoic acid; sertoli cell; spermatogenesis; ubiquitin; ubiquitin ligase.