Subcellular localization of phospholipase Cz in human sperm and its absence in DPY19L2-deficient sperm are consistent with its role in oocyte activation

Jessica Escoffier, Sandra Yassine, Hoi Chang Lee, Guillaume Martinez, Julie Delaroche, Charles Coutton, Thomas Karaouzéne, Raoudha Zouari, Catherine Metzler-Guillemain, Karin Pernet-Gallay, Sylviane Hennebicq, Pierre F. Ray, Rafael Fissore, Christophe Arnoult*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

We recently identified the DPY19L2 gene as the main genetic cause of human globozoospermia (70%) and described that Dpy19l2 knockout (KO) mice faithfully reproduce the human phenotype of globozoospermia making it an excellent model to characterize the molecular physiopathology of globozoospermia. Recent case studies on non-genetically characterized men with globozoospermia showed that phospholipase C, zeta (PLCz), the sperm factor thought to induce the Ca2+ oscillations at fertilization, was absent from their sperm, explaining the poor fertilization potential of these spermatozoa. Since 30% of globozoospermic men remain genetically uncharacterized, the absence of PLCz in DPY19L2 globozoospermic men remains to be formally established. Moreover, the precise localization of PLCz and the reasons underlying its loss during spermatogenesis in globozoospermic patients are still not understood. Herein, we show that PLCz is absent, or its presence highly reduced, in human and mouse sperm with DPY19L2-associated globozoospermia. As a consequence, fertilization with sperm from Dpy19l2 KO mice failed to initiate Ca2+ oscillations and injected oocytes remained arrested at the metaphase II stage, although a few human oocytes injected with DPY19L2-defective sperm showed formation of 2-pronuclei embryos. We report for the first time the subcellular localization of PLCz in control human sperm, which is along the inner acrosomal membrane and in the perinuclear theca, in the area corresponding to the equatorial region. Because these cellular components are absent in globozoospermic sperm, the loss of PLCz in globozoospermic sperm is thus consistent and reinforces the role of PLCz as an oocyte activation factor necessary for oocyte activation. In our companion article, we showed that chromatin compaction during spermiogenesis in Dpy19l2 KO mouse is defective and leads to sperm DNA damage. Together, these defects explain the poor fertilization potential of DPY19L2-globozoospermic sperm and the compromised developmental potential of embryos obtained using sperm from patients with a deletion of the DPY19L2 gene.

Original languageEnglish (US)
Article numbergau098
Pages (from-to)157-168
Number of pages12
JournalMolecular human reproduction
Volume21
Issue number2
DOIs
StatePublished - Aug 27 2014
Externally publishedYes

Keywords

  • Acrosome
  • DPY19L2
  • Globozoospermia
  • ICSI
  • Male infertility
  • Phospholipase C zeta

ASJC Scopus subject areas

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

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