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Subcellular localization of phospholipase Cζ in human sperm and its absence in DPY19L2-deficient sperm are consistent with its role in oocyte activation.
Mol Hum Reprod. 2015 Feb; 21(2):157-68.MH

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 (PLCζ), the sperm factor thought to induce the Ca(2+) 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 PLCζ in DPY19L2 globozoospermic men remains to be formally established. Moreover, the precise localization of PLCζ and the reasons underlying its loss during spermatogenesis in globozoospermic patients are still not understood. Herein, we show that PLCζ 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 Ca(2+) 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 PLCζ 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 PLCζ in globozoospermic sperm is thus consistent and reinforces the role of PLCζ 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.

Authors+Show Affiliations

Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France.Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France.Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, 661 North Pleasant Street, Amherst, MA 01003, USA.Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France.Université Grenoble Alpes, Grenoble F-38000, France Grenoble Institut des Neurosciences, INSERM U.836, F-38000 Grenoble, France.Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France CHU de Grenoble, UF de Génétique Chromosomique, Grenoble F-38000, France.Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France.Clinique des Jasmins, 23, Av. Louis BRAILLE, 1002 Tunis, Tunisia.Aix-Marseille Université-Inserm UMR 910, Génétique Médicale et Génomique Fonctionnelle, 13385 Marseille Cedex 5, France APHM Hôpital La Conception, Gynépôle, Laboratoire de Biologie de la Reproduction - CECOS, 13385 Marseille Cedex 5, France.Université Grenoble Alpes, Grenoble F-38000, France Grenoble Institut des Neurosciences, INSERM U.836, F-38000 Grenoble, France.Université Grenoble Alpes, Grenoble F-38000, France CHU de Grenoble, Centre d'AMP-CECOS, BP217, Grenoble Cedex 9 F-38043, France.Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France CHU de Grenoble, UF de Biochimie et Génétique Moléculaire, Grenoble F-38000, France.Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, 661 North Pleasant Street, Amherst, MA 01003, USA.Université Grenoble Alpes, Grenoble F-38000, France Equipe 'Andrologie, Génétique et Cancer' Laboratoire AGIM, CNRS FRE3405, La Tronche F-38700, France christophe.arnoult@ujf-grenoble.fr.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25354701

Citation

Escoffier, Jessica, et al. "Subcellular Localization of Phospholipase Cζ in Human Sperm and Its Absence in DPY19L2-deficient Sperm Are Consistent With Its Role in Oocyte Activation." Molecular Human Reproduction, vol. 21, no. 2, 2015, pp. 157-68.
Escoffier J, Yassine S, Lee HC, et al. Subcellular localization of phospholipase Cζ in human sperm and its absence in DPY19L2-deficient sperm are consistent with its role in oocyte activation. Mol Hum Reprod. 2015;21(2):157-68.
Escoffier, J., Yassine, S., Lee, H. C., Martinez, G., Delaroche, J., Coutton, C., Karaouzène, T., Zouari, R., Metzler-Guillemain, C., Pernet-Gallay, K., Hennebicq, S., Ray, P. F., Fissore, R., & Arnoult, C. (2015). Subcellular localization of phospholipase Cζ in human sperm and its absence in DPY19L2-deficient sperm are consistent with its role in oocyte activation. Molecular Human Reproduction, 21(2), 157-68. https://doi.org/10.1093/molehr/gau098
Escoffier J, et al. Subcellular Localization of Phospholipase Cζ in Human Sperm and Its Absence in DPY19L2-deficient Sperm Are Consistent With Its Role in Oocyte Activation. Mol Hum Reprod. 2015;21(2):157-68. PubMed PMID: 25354701.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subcellular localization of phospholipase Cζ in human sperm and its absence in DPY19L2-deficient sperm are consistent with its role in oocyte activation. AU - Escoffier,Jessica, AU - Yassine,Sandra, AU - Lee,Hoi Chang, AU - Martinez,Guillaume, AU - Delaroche,Julie, AU - Coutton,Charles, AU - Karaouzène,Thomas, AU - Zouari,Raoudha, AU - Metzler-Guillemain,Catherine, AU - Pernet-Gallay,Karin, AU - Hennebicq,Sylviane, AU - Ray,Pierre F, AU - Fissore,Rafael, AU - Arnoult,Christophe, Y1 - 2014/10/29/ PY - 2014/10/31/entrez PY - 2014/10/31/pubmed PY - 2015/10/20/medline KW - DPY19L2 KW - ICSI KW - acrosome KW - globozoospermia KW - male infertility KW - phospholipase C zeta SP - 157 EP - 68 JF - Molecular human reproduction JO - Mol. Hum. Reprod. VL - 21 IS - 2 N2 - 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 (PLCζ), the sperm factor thought to induce the Ca(2+) 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 PLCζ in DPY19L2 globozoospermic men remains to be formally established. Moreover, the precise localization of PLCζ and the reasons underlying its loss during spermatogenesis in globozoospermic patients are still not understood. Herein, we show that PLCζ 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 Ca(2+) 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 PLCζ 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 PLCζ in globozoospermic sperm is thus consistent and reinforces the role of PLCζ 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. SN - 1460-2407 UR - https://www.unboundmedicine.com/medline/citation/25354701/Subcellular_localization_of_phospholipase_Cζ_in_human_sperm_and_its_absence_in_DPY19L2_deficient_sperm_are_consistent_with_its_role_in_oocyte_activation_ L2 - https://academic.oup.com/molehr/article-lookup/doi/10.1093/molehr/gau098 DB - PRIME DP - Unbound Medicine ER -