Multivariate analysis of male reproductive function in Inpp5b-/- mice reveals heterogeneity in defects in fertility, sperm-egg membrane interaction and proteolytic cleavage of sperm ADAMs

Matthew R. Marcello, Janice Perry Evans

Research output: Contribution to journalArticle

Abstract

Past work indicated that sperm from mice deficient in the inositol polyphosphate 5-phosphatase Inpp5b have reduced ability to fertilize eggs in vitro and reduced epididymal proteolytic processing of the sperm protein A Disintegrin and A Metalloprotease 2 (ADAM2). On the basis of these data, our central working hypothesis was that reduced ADAM cleavage would correlate with reduced sperm-egg binding and fusion and in turn with reduced male fertility in Inpp5b-/- mice. Multiple endpoints of reproductive functions [mating trials, in vitro fertilization (IVF) assays and ADAM2 and ADAM3 cleavage] were investigated on a male-by-male basis, with pair-wise correlation analysis used to assess the relationships between these various parameters. Motile sperm from Inpp5b-/- mice showed significantly reduced fertilization of zona pellucida-free eggs due to reduced binding to the egg plasma membrane and subsequent fusion. Localization of a mouse sperm protein required for gamete fusion, IZUMO1, appears normal in Inpp5b-null sperm. To our surprise and differing from previous reports, we found that ADAM cleavage was only modestly impaired in numerous Inpp5b-null males and varied between individual animals. Performance in mating trials also differed from past reports. The pair-wise correlation analysis revealed that ADAM2 and ADAM3 cleavage was positively correlated, suggesting that processing of these proteins occurs by related/identical mechanisms, but otherwise, there were few correlations between the reproductive endpoints examined here. Nevertheless, this work provides detailed analysis of the Inpp5b-/- phenotype and also a blueprint for multivariate analysis to examine relationships between molecular characteristics and in vitro and in vivo physiological functions.

Original languageEnglish (US)
Article numbergaq029
Pages (from-to)492-505
Number of pages14
JournalMolecular Human Reproduction
Volume16
Issue number7
DOIs
StatePublished - Apr 19 2010

Keywords

  • A Disintegrin and A Metalloprotease
  • Fertilization
  • Inositol polyphosphate 5-phosphatase knockout mice
  • IZUMO1
  • Sperm-egg interaction

ASJC Scopus subject areas

  • Molecular Biology
  • Embryology
  • Cell Biology
  • Genetics
  • Developmental Biology
  • Reproductive Medicine
  • Obstetrics and Gynecology

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