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

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 ␣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 ␣1͞␣ 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.testis ͉ apoptosis ͉ lissencephaly

Inactivation of a Testis-specific Lis1 Transcript in Mice Prevents Spermatid Differentiation and Causes Male Infertility

“…Two recent studies (22,48) demonstrated that both catalytic subunits of PAF-AH 1B are expressed in testis and mutants lacking the ␣2 or ␣2 and ␣1 subunits exert male infertility and marked loss of germ cells at an early stage of spermatogenesis. These findings suggest that Lis1 may mediate its function in testis as part of the PAF-AH complex.…”

The cellular roles of the lissencephaly gene LIS1, and what they tell us aboutbrain development

“…The LIS1 polypeptide was initially identified as a stoichiometric component of purified platelet-activating factor acetyl-hydrolase (PAFAH)-1b (Hattori et al 1994), an enzyme involved in deactivation of the lipid messenger platelet-activating factor. Mice null for the catalytic subunits of PAFAH-1b showed no apparent brain developmental phenotype (Koizumi et al 2003;Yan et al 2003), however, suggesting that some other LIS1 function is responsible for lissencephaly. An ortholog of LIS1, NudF, was independently identified as a regulator of cytoplasmic dynein function in the filamentous fungus Aspergillus nidulans (Xiang et al 1995).…”

Novel isoforms of intracellular platelet activating factor acetylhydrolase (PAFAH1b2) in human testis; encoded by alternatively spliced mRNAs

“…It has been suggested that Paf-ah-Ib's activity in spermatogenesis, apoptosis, and neuronal migration may not rest entirely in its catalytic ability to reduce PAF levels but that it may act as a signaling complex in conjunction with other proteins (4,5,14). The Alpha-2 isoforms described herein may introduce levels of regulation and interaction beyond Pafah1b2's catalytic activity imparting additional, as yet uncharacterized, links to intracellular signaling pathways in testis and other tissues.…”

“…Male infertility was due to the impairment of spermatogenesis at several stages of development. Homozygous knockout of the Alpha-1 subunit does not impair fertility or spermatogenesis (14,30). The possibility arises that the modified protein encoded by SpV-2 either alone or in a complex with SpV-1 or canonical Pafah-Ib subunits, imparts the characteristics necessary for Pafah1b2's specialized roles in spermatogenesis.…”

“…It has been suggested that the alpha subunits of paf-ah-Ib may also effect other intracellular processes utilizing properties unrelated to their catalytic capabilities (14).…”