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Published online before print May 15, 2008

0031-6997/08/6002-146-180$7.00
Pharmacol Rev 60:146-180, 2008

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Anchoring Junctions As Drug Targets: Role in Contraceptive Development

Dolores D. Mruk, Bruno Silvestrini and C. Yan Cheng

Population Council, Center for Biomedical Research, New York, New York (D.D.M., C.Y.C.); and The Noopolis Foundation, Rome, Italy (B.S.)

Abstract
I. Introduction
II. General Review of Anchoring Junctions
    A. Cell-Cell Actin-Based Adherens Junctions
        1. Cadherin-Catenin Multiprotein Complex.
            a. Classic cadherins.
            b. Other cadherin family members.
            c. Classic catenins.
            d. p120 catenin family.
        2. Nectin-Afadin Multiprotein Complex.
    B. Cell-Cell Intermediate Filament-Based Desmosome Junctions
        1. Desmosomal Cadherins.
        2. Armadillo Proteins.
        3. Plakins.
    C. Cell-Matrix Intermediate Filament-Based Hemidesmosomes
    D. Cell-Matrix Actin-Based Focal Contacts
III. Review of Anchoring Junctions in the Testis and Their Regulation
    A. Cellular Organization of the Seminiferous Epithelium in the Testis
    B. Concept of the Blood-Testis Barrier
    C. The Ectoplasmic Specialization, a Testis-Specific Anchoring Junction
        1. Integrin-Laminin Multiprotein Complex.
    D. Regulation of Anchoring Junctions in the Testis
        1. Phosphatases and Kinases.
        2. Cytokines and Growth Factors.
        3. Small GTPases.
        4. Proteases and Protease Inhibitors.
IV. Targeting Anchoring Junctions in the Testis for Male Contraceptive Development
    A. Background
    B. Adjudin Efficacy, Dosing, and Reversibility of Antifertility Effects
    C. Bioavailability, Tissue Distribution, and Metabolic Clearance of Adjudin
    D. Acute and Subchronic Toxicity
    E. Mechanism of Adjudin Action in the Testis: The Current Model
    F. Current Status of Adjudin Research
    G. Additional Comments
V. Concluding Remarks
In multicellular organisms, cell-cell interactions are mediated in part by cell junctions, which underlie tissue architecture. Throughout spermatogenesis, for instance, preleptotene leptotene spermatocytes residing in the basal compartment of the seminiferous epithelium must traverse the blood-testis barrier to enter the adluminal compartment for continued development. At the same time, germ cells must also remain attached to Sertoli cells, and numerous studies have reported extensive restructuring at the Sertoli-Sertoli and Sertoli-germ cell interface during germ cell movement across the seminiferous epithelium. Furthermore, the proteins and signaling cascades that regulate adhesion between testicular cells have been largely delineated. These findings have unveiled a number of potential "druggable" targets that can be used to induce premature release of germ cells from the seminiferous epithelium, resulting in transient infertility. Herein, we discuss a novel approach with the aim of developing a nonhormonal male contraceptive for future human use, one that involves perturbing adhesion between Sertoli and germ cells in the testis.

Address correspondence to: Dr. Dolores D. Mruk, PhD, Population Council, Center for Biomedical Research, The Mary M. Wohlford Laboratory for Male Contraceptive Research, 1230 York Avenue, New York, NY 10065. E-mail: d-mruk{at}popcbr.rockefeller.edu






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