期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：12
页码：7189-7194
DOI：10.1073/pnas.1236145100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 1 and 2 subunits] and structurally resembles a GTP-hydrolyzing protein. Besides the brain, transcripts for Lis1, 1, and 2 are localized to meiotic and early haploid germ cells. Here, we report disruptions of the 2 (Pafah1b2) and 1 (Pafah1b3) genes in mice. Male mice homozygous null for 2(2-/-) are infertile, and spermatogenesis is disrupted at mid- or late pachytene stages of meiosis or early spermiogenesis. Whereas mice homozygous mutant for 1(1-/-) have normal fertility and normal spermatogenesis, those with disruptions of both 1 and 2 (1-/-2-/-) 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 2-/- and 1-/-2-/- mice. Lowering Lis1 levels by inactivating one allele of Lis1 in 2 null or 1/ 2 null genetic backgrounds (i.e., 2-/-Lis1+/- or 1-/-2-/-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.
