title: Targeted disruption of intracellular type I platelet activating factor-acetylhydrolase catalytic subunits causes severe impairment in spermatogenesis.
abstract: Intracellular type I platelet activating factor-acetylhydrolase is a phospholipase that consists of a dimer of two homologous catalytic subunits alpha1 and alpha2 as well as LIS1, a product of the causative gene for type I lissencephaly. LIS1 plays an important role in neuronal migration during brain development, but the in vivo function of the catalytic subunits remains unclear. In this study, we generated alpha1- and a2-deficient mice by targeted disruption. alpha1(-/-) mice are indistinguishable from wild-type mice, whereas alpha2(-/-) male mice show a significant reduction in testis size. Double-mutant male mice are sterile because of severe impairment of spermatogenesis. Histological examination revealed marked degeneration at the spermatocyte stage and an increase of apoptotic cells in the seminiferous tubules. The catalytic subunits are expressed at high levels in testis as well as brain in mice. In wild-type mice, alpha2 is expressed in all seminiferous tubule cell types, whereas alpha1 is expressed only in the spermatogonia. This expression pattern parallels the finding that deletion of both subunits induces a marked loss of germ cells at an early spermatogenic stage. We also found that the LIS1 protein levels, but not the mRNA levels, were significantly reduced in alpha2(-/-) and double-mutant mice, suggesting that the catalytic subunits, especially alpha2, are a determinant of LIS1 expression level.
authors.affiliation: Department of Health Chemistry and Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koizumi
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Hattori
authors.forename: Tomo-O
authors.initials: TO
authors.lastname: Ishikawa
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Keizo
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D000911:Antibodies, Monoclonal; D020134:Catalytic Domain / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D010741:Phospholipases A / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D013091:Spermatogenesis / Q000502:physiology*; D013737:Testis / Q000201:enzymology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D008869:Microtubule-Associated Proteins; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse