Defect in germ cells, not in supporting cells, is the cause of male infertility in the jsd mutant mouse: proliferation of spermatogonial stem cells without differentiation

Abstract

C57BL/6 (B6)-jsd/jsd male mice are sterile because of lack of spermatogenesis. To find the cause of the deficient spermatogenesis, we have examined whether the mutation phenotype is the result of a defect in germ cells or in supporting cells using germ cell transplantation. In the seminiferous tubules of B6-jsd/jsd mutant mice, donor germ cells derived from the wild type GFP transgenic mouse (B6-+/+GFP) were able to undergo complete spermatogenesis, indicating that the juvenile spermatogonial depletion (jsd/jsd) mouse possesses normal supporting cell functions. In contrast, undifferentiated spermatogonia derived from B6-jsd/jsd mice were unable to differentiate in the seminiferous tubules of W/W v mice, even if the mutant germ cells successfully settled in the tubules. These results demonstrate that the deficiency in spermatogenesis of B6-jsd/jsd mice can be ascribed to a defect in spermatogonia but not in their supporting cell environment. Furthermore, the defect in B6-jsd/jsd spermatogonia is not in their ability to proliferate, but in their differentiation and may result from their hypersensitivity to high concentrations of androgen in the testis.

Transplantation of spermatogonial stem cells isolated from leukemic mice restores fertility without inducing leukemia

“…With respect to the third hurdle, a procedure for transplanting germ cells so that they undergo normal spermatogenesis has been established in animals (8,9,19), and this normal spermatogenesis was further confirmed in our study. We too have reported normal spermatogenesis of transplanted germ cells (13,14,20). We know the resulting mature sperm had the normal ability to fertilize because the rate of embryos reaching full term in this study (28.6%) was the same as that of embryos constructed with normal sperm (21).…”

“…To overcome this problem, testicular tissues could be harvested before treatment from prepubertal patients who have only spermatogonia and spermatocytes, then cryopreserved; immature germ cells could somehow be matured either by autotransplantation, in vitro maturation, or xenografting. Because the seminiferous tubules of testes contain functional Sertoli cells even after chemotherapy or radiation (10,13,14), autotransplantation into seminiferous tubules would mature immature germ cells to become sperm. However, there are at least 3 hurdles to overcome before this idea can be applied clinically.…”

CCR4-Associated Factor CAF1 Is an Essential Factor for Spermatogenesis

“…mCAF1 Ϫ/Ϫ mice did not exhibit a stage-specific arrest of spermatogenesis as generally observed in mutant mice in which male sterility is due to a germinal cell primary defect (7,14,22,39,49,57,58,60,64,72,77). The absence of a stage-specific defect in mCAF1 Ϫ/Ϫ pathology would thus suggest a defect in seminiferous tubule homeostasis.…”

“…Furthermore, mCAF1 was expressed in highly purified Sertoli and Leydig cells at 19 days. Testes obtained from mice at different ages (10,15,20,30,45,60,90, and 120 days) showed the presence of mCAF1 mRNA at every age tested (Fig. 4C).…”

Evolutionarily Conserved Mammalian Adenine Nucleotide Translocase 4 Is Essential for Spermatogenesis

“…Multiple autosomal retrogenes of X chromosome origin have been reported as candidates potentially compensating for the absence of essential sexlinked gene expression during male meiosis, as exemplified by the Pgk1/Pgk2 gene family (47)(48)(49)(50). Although such retrogenes are considered to positively support male meiosis, there has been only one report so far (Utp14b) to clearly demonstrate the absolute necessity of such retrogenes in male meiosis (51,52). It seems that even Pgk2 null mice demonstrate minimal male infertility (depending on genetic background) mainly because of a sperm motility defect (53).…”