Abstract
During the release of sperm at spermiation, a biologically active F5-peptide, which can disrupt the Sertoli cell tight junction (TJ) permeability barrier, is produced at the site of the degenerating apical ES (ectoplasmic specialization). This peptide coordinates the events of spermiation and blood-testis barrier (BTB) remodeling at stage VIII of the epithelial cycle, creating a local apical ES-BTB axis to coordinate cellular events across the epithelium. The mechanism(s) by which F5-peptide perturbs BTB restructuring, and its involvement in apical ES dynamics remain unknown. F5-peptide, besides perturbing BTB integrity, was shown to induce germ cell release from the epithelium following its efficient in vivo overexpression in the testis. Overexpression of F5-peptide caused disorganization of actin- and microtubule (MT)-based cytoskeletons, mediated by altering the spatiotemporal expression of actin binding/regulatory proteins in the seminiferous epithelium. F5-peptide perturbed the ability of actin microfilaments and/or MTs from converting between their bundled and unbundled/defragmented configuration, thereby perturbing adhesion between spermatids and Sertoli cells. Since apical ES and basal ES/BTB are interconnected through the underlying cytoskeletal networks, this thus provides an efficient and novel mechanism to coordinate different cellular events across the epithelium during spermatogenesis through changes in the organization of actin microfilaments and MTs. These findings also illustrate the potential of F5-peptide being a male contraceptive peptide for men.
Highlights
IntroductionEarlier studies have shown that the events of spermiation and BTB (blood-testis barrier) remodeling that take place at the opposite ends of the seminiferous epithelium at stage VIII of the epithelial cycle are coordinated through an autocrine-based local axis known as the apical ES-BTB-basement membrane axis (for reviews, see [1, 2])
Earlier studies have shown that the events of spermiation and blood-testis barrier (BTB) remodeling that take place at the opposite ends of the seminiferous epithelium at stage VIII of the epithelial cycle are coordinated through an autocrine-based local axis known as the apical ES-BTB-basement membrane axis
It appears that F5-peptide can serve as a novel male contraceptive peptide that is endogenously produced since high doses of F5-peptide administered to the testis is known to reversibly perturb the BTB function that leads to massive germ cell exfoliation [5]. This finding is consistent with earlier studies using toxicant models in which permanent BTB disruption led to germ cell exfoliation and male infertility including treatment of rodents with cadmium [18, 19, 28] or glycerol [29]
Summary
Earlier studies have shown that the events of spermiation and BTB (blood-testis barrier) remodeling that take place at the opposite ends of the seminiferous epithelium at stage VIII of the epithelial cycle are coordinated through an autocrine-based local axis known as the apical ES-BTB-basement membrane axis (for reviews, see [1, 2]). A synthetic peptide based on F5-peptide was shown to penetrate through the Sertoli cell BTB via the drug transporter Slc15a1 [6]. This observation is important since F5-peptide is generated endogenously through cleavage of the laminin-γ3 chain, a spermatidspecific protein at the apical ES in rodent testes [7,8,9]
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