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Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis
- Source :
- PLoS Genetics, PLoS Genetics, 2017, 13 (6), ⟨10.1371/journal.pgen.1006803⟩, PLoS Genetics, Vol 13, Iss 6, p e1006803 (2017), PLoS Genetics, Public Library of Science, 2017, 13 (6), ⟨10.1371/journal.pgen.1006803⟩, PLOS Genetics
- Publication Year :
- 2017
- Publisher :
- HAL CCSD, 2017.
-
Abstract
- Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes.<br />Author summary Spermatogenesis defects are a common cause of male sterility. Spermatogenesis occurs in the seminiferous tubules of the testes and involves adhesive interactions between developing germ cells and Sertoli cells. Knock-out mouse models identified several adhesion molecules that are critically involved in spermatogenesis. We previously demonstrated that the Junctional Adhesion Molecule-C (JAM-C) plays a crucial role in establishing spermatids polarity. The latter involves rearrangements of the Golgi apparatus in spermatids which contribute to acrosome formation. The present study demonstrated that the C-terminal cytosolic region of JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55) encoded by Gorasp2 and that spermatogenesis was impaired in Gorasp2-deficient mice. We developed an inhibitor of GRASP55 interaction with JAM-C and demonstrated that treatment of wild-type mice with the inhibitory compound induced germ cell loss. Therefore, the male infertility-associated pathway identified in this study is important not only from a genetic point of view, but also as a potential target for male contraception.
- Subjects :
- Male
Physiology
[SDV]Life Sciences [q-bio]
Golgi Apparatus
Mice
Animal Cells
Reproductive Physiology
Spermatocytes
Medicine and Health Sciences
Cell Cycle and Cell Division
Testes
Cells, Cultured
Staining
Chromosome Biology
Intracellular Signaling Peptides and Proteins
Specimen preparation and treatment
Spermatids
humanities
Protein Transport
Meiosis
Seminiferous tubules
Cell Processes
cardiovascular system
Cellular Types
Anatomy
Cellular Structures and Organelles
Genital Anatomy
Protein Binding
Research Article
endocrine system
lcsh:QH426-470
education
Immunoglobulins
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Germ cells
Acrosomes
Animals
Spermatogenesis
Binding Sites
fungi
Reproductive System
DAPI staining
Membrane Proteins
Biology and Life Sciences
Cell Biology
Spermatogonia
Sperm
Mice, Inbred C57BL
Research and analysis methods
lcsh:Genetics
Nuclear staining
Carrier Proteins
Cell Adhesion Molecules
Subjects
Details
- Language :
- English
- ISSN :
- 15537390 and 15537404
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics, PLoS Genetics, 2017, 13 (6), ⟨10.1371/journal.pgen.1006803⟩, PLoS Genetics, Vol 13, Iss 6, p e1006803 (2017), PLoS Genetics, Public Library of Science, 2017, 13 (6), ⟨10.1371/journal.pgen.1006803⟩, PLOS Genetics
- Accession number :
- edsair.pmid.dedup....df9b7e5874e1d7d7e1e371aa2fe2fd3b