Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis

Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7189-94. doi: 10.1073/pnas.1236145100. Epub 2003 May 29.

Abstract

Platelet-activating factor (PAF) has been shown to affect sperm motility and acrosomal function, thereby altering fertility. PAF acetylhydrolase 1b (PAFAH1B) hydrolyzes PAF and is composed of three subunits [the lissencephaly (LIS1) protein and alpha1 and alpha2 subunits] and structurally resembles a GTP-hydrolyzing protein. Besides the brain, transcripts for Lis1, alpha1, and alpha2 are localized to meiotic and early haploid germ cells. Here, we report disruptions of the alpha2 (Pafah1b2) and alpha1 (Pafah1b3) genes in mice. Male mice homozygous null for alpha2(alpha2-/-) are infertile, and spermatogenesis is disrupted at mid- or late pachytene stages of meiosis or early spermiogenesis. Whereas mice homozygous mutant for alpha1(alpha1-/-) have normal fertility and normal spermatogenesis, those with disruptions of both alpha1 and alpha2 (alpha1-/-alpha2-/-) manifest an earlier disturbance of spermatogenesis with an onset at preleptotene or leptotene stages of meiosis. Testicular Lis1 protein levels are up-regulated in the alpha2-/- and alpha1-/-alpha2-/- mice. Lowering Lis1 levels by inactivating one allele of Lis1 in alpha2 null or alpha1/alpha 2 null genetic backgrounds (i.e., alpha2-/-Lis1+/- or alpha1-/-alpha2-/-Lis1+/- mice) restored spermatogenesis and male fertility. Our data provide evidence for unique roles of the PAFAH1B complex and, particularly, the lissencephaly protein Lis1 in spermatogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Animals
  • Apoptosis
  • Gene Expression
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / physiology*
  • Phenotype
  • Phospholipases A / deficiency
  • Phospholipases A / genetics
  • Phospholipases A / physiology*
  • Platelet Activating Factor / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Spermatogenesis / genetics
  • Spermatogenesis / physiology*
  • Testis / abnormalities
  • Testis / metabolism
  • Testis / pathology

Substances

  • Microtubule-Associated Proteins
  • Platelet Activating Factor
  • RNA, Messenger
  • Phospholipases A
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse