Genetic factors contributing to defective spermatogonial differentiation in juvenile spermatogonial depletion (Utp14bjsd) mice

Male mice that are homozygous for the juvenile spermatogonial depletion (jsd) mutation in the Utp14b gene undergo several waves of spermatogenesis. However, spermatogonial differentiation ceases and in adults, spermatogonia are the only germ cells that remain. To understand further the blockage in spermatogonial differentiation in Utp14b(jsd) mutant mice, we correlated the rate and severity of spermatogonial depletion and the restoration of spermatogenesis following the suppression of testosterone or elevation of testicular temperature with the genetic background. Testes from Utp14b(jsd) mutant mice on B6, C3H, and mixed C3H-B6-129 (HB129) genetic backgrounds all showed steady decreases in the numbers of normal spermatogonia between 8 wk and 20 wk of age. The percentages of tubules with differentiating germ cells were higher and the spermatogonia were more advanced in C3H- background than in B6- or HB129-background Utp14b(jsd) mice. Genetic crosses showed that the source of the Y chromosome was a major factor in determining the severity of spermatogonial depletion in Utp14b(jsd) mutant mice. When Utp14b(jsd) mutants were subjected to total androgen ablation or unilateral cryptorchidization, spermatogenic development recovered markedly in the C3H and HB129 background but showed less recovery in the B6-background mice. The differences noted between the strains in terms of the severity of spermatogonial depletion were not dependent upon testosterone level or scrotal temperature but correlated with the magnitudes of the effects of elevated temperature on normal and Utp14b(jsd) mutant spermatogenic cells. Thus, the abilities of germ cells in certain strains to survive elevated temperatures may be related to their abilities to maintain some degree of differentiation potential after the Utp14b(jsd) gene is mutated.     

Gene expression alterations by conditional knockout of androgen receptor in adult Sertoli cells of Utp14b jsd/jsd (jsd) mice

Spermatogenesis is dependent primarily on testosterone action on the Sertoli cells, but the molecular mechanisms have not been identified. Attempts to identify testosterone-regulated target genes in Sertoli cells have used microarray analysis of gene expression in mice lacking the androgen receptor (AR) in Sertoli cells (SCARKO) and wild-type mice, but the analyses have been complicated both by alteration of germ cell composition of the testis when pubertal or adult mice were used and by differences in Sertoli-cell gene expression from the expression in adults when prepubertal mice were used. To overcome these limitations and identify AR-regulated genes in adult Sertoli cells, we compared gene expression in adult jsd (Utp14b jsd/jsd, juvenile spermatogonial depletion) mouse testes and with that in SCARKO-jsd mouse testes, since their cellular compositions are essentially identical, consisting of only type A spermatogonia and somatic cells. Microarray analysis identified 157 genes as downregulated and 197 genes as upregulated in the SCARKO-jsd mice compared to jsd mice. Some of the AR-regulated genes identified in the previous studies, including Rhox5, Drd4, and Fhod3, were also AR regulated in the jsd testes, but others, such as proteases and components of junctional complexes, were not AR regulated in our model. Surprisingly, a set of germ cell–specific genes preferentially expressed in differentiated spermatogonia and meiotic cells, including Meig1, Sycp3, and Ddx4, were all upregulated about 2-fold in SCARKO-jsd testes. AR-regulated genes in Sertoli cells must therefore be involved in the regulation of spermatogonial differentiation, although there was no significant differentiation to spermatocytes in SCARKO-jsd mice. Further gene ontogeny analysis revealed sets of genes whose changes in expression may be involved in the dislocation of Sertoli cell nuclei in SCARKO-jsd testes.