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Disrupted sperm function and fertilin beta processing in mice deficient in the inositol polyphosphate 5-phosphatase
E Hellsten1, J P Evans, D J Bernard
1Genetic Diseases Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
Abstract:
Inpp5b is an ubiquitously expressed type II inositol polyphosphate 5-phosphatase. We have disrupted the Inpp5b gene in mice and found that homozygous mutant males are infertile. Here we examine the causes for the infertility in detail. We demonstrate that sperm from Inpp5b(-/-) males have reduced motility and reduced ability to fertilize eggs, although capacitation and acrosome exocytosis appear to be normal. In addition, fertilin beta, a sperm surface protein involved in sperm-egg membrane interactions that is normally proteolytically processed during sperm transit through the epididymis, showed reduced levels of processing in the Inpp5b(-/-) animals. Inpp5b was expressed in the Sertoli cells and epididymis and at low levels in the developing germ cells; however, mice lacking Inpp5b in spermatids and not in other cell types generated by conditional gene targeting, were fully fertile. The abnormalities in mutant sperm function and maturation appear to arise from defects in the functioning of Sertoli and epididymal epithelial cells. Our results directly demonstrate a previously unknown role for phosphoinositides in normal sperm maturation beyond their previously characterized involvement in the acrosome reaction. Inpp5b(-/-) mice provide an excellent model to study the role of Sertoli and epididymal epithelial cells in the differentiation and maturation of sperm.
Insights
Inositol polyphosphate 5-phosphatase (Inpp5b) is crucial for male fertility. Mice lacking Inpp5b exhibit infertility due to impaired sperm motility and fertilization, highlighting a new role for phosphoinositides in sperm maturation.
Area of Science:
- Reproductive Biology
- Molecular Genetics
- Cell Biology
Background:
- Inositol polyphosphate 5-phosphatase (Inpp5b) is widely expressed and involved in phosphoinositide metabolism.
- The precise role of Inpp5b in male reproductive function and sperm maturation is not fully understood.
Purpose of the Study:
- To investigate the causes of infertility in Inpp5b-deficient mice.
- To elucidate the specific functions of Inpp5b in sperm development and function.
Main Methods:
- Generation and phenotypic analysis of Inpp5b knockout mice.
- Assessment of sperm motility, capacitation, acrosome exocytosis, and fertilization ability.
- Analysis of fertilin beta processing and Inpp5b expression in reproductive tissues.
Main Results:
- Inpp5b(-/-) male mice are infertile with significantly reduced sperm motility and fertilization capacity.
- Sperm from mutant mice show defects in fertilin beta processing, a key protein for sperm-egg interaction.
- Conditional gene targeting revealed that Inpp5b is essential in Sertoli and epididymal cells, but not germ cells, for fertility.
Conclusions:
- Inpp5b plays a critical, previously unrecognized role in sperm maturation and function, independent of the acrosome reaction.
- Defects in Sertoli and epididymal epithelial cells due to Inpp5b absence underlie the observed sperm abnormalities.
- Inpp5b(-/-) mice serve as a valuable model for studying phosphoinositide roles in sperm differentiation and maturation.