Role of integrins, tetraspanins, and ADAM proteins during the development of apoptotic bodies by spermatogenic cells

Abraham L. Kierszenbaum, Carolina Rosselot, Eugene Rivkin, Laura L. Tres

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

We have previously reported that Sertoli cell geometric changes induced by a Fas (CD95) agonist or by restricting Sertoli cell spreading can trigger spermatogenic cell detachment from Sertoli cell surfaces and initiate a programmed cell death sequence. Here, we have focused on ADAM proteins, tetraspanins CD9 and CD81, and the integrin β1 subunit, which is co-expressed in testis with integrin α3 and integrin α6 subunits, to understand how these molecules may stabilize spermatogenic cell attachment to Sertoli cell surfaces. Like ADAM proteins, integrin β1, α3, and α6 subunits, and CD9 and CD81 transcripts are expressed in the fetal testis and throughout testicular maturation, as well as, in Sertoli- spermatogenic cell co-cultures. Prespermatogonia (gonocytes) display CD9 and CD81 immunoreactive sites. Integrin α6 subunit transcripts have unusual developmental characteristics: fetal testis expresses the integrin α6B isoform exclusively. In contrast, the integrin α6B isoform co-exists with the integrin α6A isoform in prepubertal testes and Sertoli-spermatogenic cell co-cultures. A blocking anti body targeting the extracellular domain (N-terminal) of the integrin β1 subunit causes rapid contraction of Sertoli cells leading to the gradual detachment of associated spermatogenic cells. In contrast, predicted active site peptides targeting the disintegrin domain of ADAM 1, ADAM 2, ADAM 3 (cyritestin), ADAM 4, ADAM 5, ADAM 6, and ADAM 15 (metragidin) do not disturb significantly the attachment of spermatogenic cells to Sertoli cell surfaces. Spermatogenic cells dis-lodged from their attachment sites by the integrin β1 subunit blocking antibody display annexin V immunoreactivity, a sign of early apoptosis. Time-lapse video-microscopy demonstrates that the removal by apoptosis of a single member of a spermatogenic cell cohort interconnected by cytoplasmic bridges does not affect the remaining members of the cohort. During spermatogenic cell apoptosis, integrin β1, α3, and α6 subunits, and tetraspanins CD9 and C81 become displaced away from the developing apoptotic bodies. In contrast, the intermediate filament protein Sak57, a keratin 5 ortholog, concentrates in the developing apoptotic bodies. We propose that the redistribution of integrin-tetraspanin complexes during spermatogenic cell apoptosis may be evidence of a signaling cascade initiated by Sertoli cell geometric changes. As a result, Sertoli cell reduction in surface area may be a limiting factor of spermatogenic cell survival and in the developmental regulation of spermatogenic cell progenies in the intact seminiferous epithelium.

Original languageEnglish
Pages (from-to)906-917
Number of pages12
JournalMolecular Reproduction and Development
Volume73
Issue number7
DOIs
StatePublished - Jul 2006
Externally publishedYes

Keywords

  • Actin fragmentation
  • Cell-cell anchorage
  • Sertoli cell geometry
  • Testicular development

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