Male germ cell-specific knockout of cholesterogenic Cytochrome P450 lanosterol 14[alpha]-demethylase (Cyp51)
Keber, Rok, univ. dipl. biol., 1982- ...
Cytochrome P450 lanosterol 14alpha-demethylase (CYP51) and its products meiosis-activating sterols (MAS) were hypothesized by previous in vitro studies to have an important role in regulating meiosis ...and reproduction. To test this in vivo we generated a conditional male germ cell-specific knockout of the gene Cyp51 in the mouse. High excision efficiency of Cyp51 allele in germ cells resulted in 85-89% downregulation of Cyp51 mRNA and protein levels in germ cells. Quantitative metabolic profiling revealed significantly higher levels of CYP51 substrates lanosterol and 24,25-dihydrolanosterol and substantially diminished levels of MAS, the immediate products of CYP51. However, germ cell-specific ablation of Cyp51, leading to lack of MAS, did not affect testicular morphology, daily sperm production or reproductive performance in males. It is plausible that due to the similar structures of cholesterol intermediates, previously proposed biological function of MAS in meiosis progression can be replaced by some other yet unidentified functionally redundant lipid molecule(s). Our results using the germ cell-specific knockout model provides first in vivo evidence that the de novo synthesis of MAS and cholesterol in male germ cells is most likely not essential for spermatogenesis and reproduction and that MAS, originating from germ cells do not cell-autonomously regulate spermatogenesis and fertility.
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