Cyclic adenosine 3 ',5 '-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14 alpha-demethylase (CYP51) in spermatids

Lanosterol 14 alpha-demethylase (CYP51) produces MAS sterols, intermediates in cholesterol biosynthesis that can reinitiate meiosis in mouse oocytes. As a cholesterogenic gene, CYP51 is regulated by a sterol/sterol-regulatory element binding protein (SREBP)-dependent pathway in liver and other somat ic tissue. In testis, however, cAMP/cAMP-responsive element modulator CREM tau-dependent regulation of CYP51 predominates, leading to increased levels of shortened CYP51 mRNA transcripts. CREM-/- mice lack the abundant germ c ell-specific CYP51 mRNAs in testis while expression of somatic CYP51 transc ripts is unaffected. The mRNA levels of squalene synthase tan enzyme preced ing CYP51 in cholesterol biosynthesis in testis of CREM-/- mice are unchang ed as compared with wild-type animals, showing that regulation by CREM tau is not characteristic for all cholesterogenic genes expressed during sperma togenesis. The -334/+314 bp CYP51 region can mediate both the sterol/SREBP- dependent as well as the cAMP/CREM tau-dependent transcriptional activation . SREBP-1a from somatic cell nuclear extracts binds to a conserved CYP51-SR E1 element in the CYP51 proximal promoter. The cAMP-dependent transcription al activator CREM tau from germ cell nuclear extracts binds to a conserved CYP51-CRE2 element while no SREBP-1 binding is observed in germ cells. The two regulatory pathways mediating expression of CYP51 describe this gene as a cholesterogenic gene (SREBP-dependent expression in liver and other soma tic cells) and also as a haploid expressed gene (CREM tau-dependent express ion in haploid male germ cells). While in somatic cells all genes involved in cholesterol biosynthesis are regulated coordinately by the sterol/SREBP- signaling pathway, male germ cells contain alternate routes to control expr ession of cholesterogenic genes.