Male germ cell-specific knockout of cholesterogenic cytochrome P450 lanosterol 14α-demethylase (Cyp51)

Abstract

sexes have been a matter of intense investigation. Early experiments suggested that a diffusible, sex-unspecifi c meiosis-inducing substance is produced by gonads of both sexes but induces meiotic initiation only in female germ cells. It was suggested that meiosis in the prespermatogonia could be blocked by the antagonistic action of meiosis-preventing substance, secreted by testicular cords ( 1, 2 ). In 1995, two structurally related sterols, termed meiosis-activating sterols (MAS), with the ability to trigger the resumption of meiosis in mouse oocytes cultured in vitro, were identifi ed ( 3 ). Follicular fl uid meiosis-activating sterol (FF-MAS), isolated from human follicular fl uid, and testis meiosis-activating sterol (T-MAS), isolated from bull testes, were the fi rst reported sterol precursors with potential biological activity and the fi rst compounds with meiosis-activating potency. Based on the sex-and species-unspecifi c action of MAS, a hypothesis about the important role of MAS in reproduction emerged ( 3, 4 ). However, follow-up in vitro experiments have provided evidence that MAS might not be absolutely essential for gonadotropin-mediated resumption of meiosis ( 5 ). In contrast, some studies have demonstrated that MAS and related analogs promote nuclear and cytoplasmic maturation of oocyte in vitro ( 6 ). Therefore, despite the existence of a relatively large body of in vitro studies indicating an important regulatory role of MAS in the onset of meiosis in oocytes, in vivo proof has not yet been provided. a Young Scientist Fellowship to R. K.; Abstract

Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways

“…t-MAS and its immediate precursor ff-MAS have been implicated as meiosis-activating sterols in the formation of male and female germ cells ( Byskov et al, 1995 ); however, the role of these precursor sterols remains controversial. Germ-cell specific ablation of Cyp51a1, the enzyme that converts lanosterol to ff-MAS ( Figure 1 ), markedly reduced testicular t-MAS concentration but had no effect on reproductive function in male mice ( Keber et al, 2013 ). The reduction in flux from t-MAS to zymosterol that we observed in mouse testes ( Figure 5 ) may be due to t-MAS being converted to another sterol (or steroid hormone), or to the secretion of t-MAS from the testes.…”

Hidden Disease Susceptibility and Sexual Dimorphism in the Heterozygous Knockout of Cyp51 from Cholesterol Synthesis

“…The Cyp51 +/− animals on the standard laboratory diet (LFnC) develop normally based on standard visual inspection and as expected they reproduce normally [18] . The Cyp51 +/− heterozygotes show a decreased expression of Cyp51 mRNA and protein compared to the Cyp51 +/+ controls on each diet ( Figure 2 ), indicating that Cyp51 is transcribed from both alleles with no compensatory mechanisms in Cyp51 +/− mice.…”

“…In humans homozygous CYP51A1 dysfunctions have not been detected so far, as they probably spontaneously abort in early development. Cyp51 is likely not essential for normal spermatogenesis [18] even if the products of lanosterol demethylation might serve as signaling sterols [19] . In humans, CYP51A1 was hemizygously deleted in a family with cerebral cavernous malformations [20] , and the gene was proposed as a candidate for the cause of pediatric cataracts [21] .…”

Retinoic acid-induced CYP51 nuclear translocation promotes meiosis prophase I process and is correlated to the expression of REC8 and STAG3 in mice

“…Germ cell-conditional deletion of Cyp51 in mice did not affect male reproductive performance. Cyp51- deleted testes were morphologically normal ( Keber et al, 2013 ). In females, CYP51 is expressed spatiotemporally in mice ovaries, exhibiting cell-type-specific expression during meiotic resumption in oocytes ( Rozman et al, 2002 ; Song et al, 2008 ).…”