Neuroplastin Expression in Male Mice Is Essential for Fertility, Mating, and Adult Testosterone Levels

Abstract

Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn−/−) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn−/− males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn−/− males support undisturbed hormonal regulation in the brain. However, Nptn−/− males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn−/− males. LH-receptor stimulation raising intracellular Ca2+ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca2+ ATPase 1 (PMCA1) in Nptn−/− Leydig cells suggests that Nptn−/− Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn−/− males, revealing that Np is essential for reproduction.