Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis.
نویسندگان
چکیده
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.
منابع مشابه
Inactivation of a testis-specific Lis1 transcript in mice prevents spermatid differentiation and causes male infertility.
Lis1 protein is the non-catalytic component of platelet-activating factor acetylhydrolase 1b (PAF-AH 1B) and associated with microtubular structures. Hemizygous mutations of the LIS1 gene cause type I lissencephaly, a brain abnormality with developmental defects of neuronal migration. Lis1 is also expressed in testis, but its function there has not been determined. We have generated a mouse mut...
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Platelet-activating factor (PAF) acetylhydrolase has been recognized as an enzyme that inactivates PAF. We developed a convenient and reproducible method for determining human serum PAF acetylhydrolase activity. The assay was based on measurement of [14C]acetate produced from 1-O-alkyl-2-[14C]-acetyl-sn-glycero-3-phosphocholine upon precipitation of the complex of radioactive substrate and albu...
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BACKGROUND AND PURPOSE Platelet-activating factor is a potent bioactive phospholipid and may play an important role in occlusive vascular diseases. To assess the inactivation of this autacoid in plasma, we measured platelet-activating factor acetylhydrolase activity in plasma low density and high density lipoproteins from patients with ischemic stroke. METHODS Low density and high density lip...
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ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 100 12 شماره
صفحات -
تاریخ انتشار 2003