Involvement of the D-Type Cyclins in Germ Cell Proliferation and Differentiation in the Mouse1

Abstract

Using immunohistochemistry, the expression of the D-type cyclin proteins was studied in the developing and adult mouse testis. Both during testicular development and in adult testis, cyclin D(1) is expressed only in proliferating gonocytes and spermatogonia, indicating a role for cyclin D(1) in spermatogonial proliferation, in particular during the G(1)/S phase transition. Cyclin D(2) is first expressed at the start of spermatogenesis when gonocytes produce A(1) spermatogonia. In the adult testis, cyclin D(2) is expressed in spermatogonia around stage VIII of the seminiferous epithelium when A(al) spermatogonia differentiate into A(1) spermatogonia and also in spermatocytes and spermatids. To further elucidate the role of cyclin D(2) during spermatogenesis, cyclin D(2) expression was studied in vitamin A-deficient testis. Cyclin D(2) was not expressed in the undifferentiated A spermatogonia in vitamin A-deficient testis but was strongly induced in these cells after the induction of differentiation of most of these cells into A(1) spermatogonia by administration of retinoic acid. Overall, cyclin D(2) seems to play a role at the crucial differentiation step of undifferentiated spermatogonia into A(1) spermatogonia. Cyclin D(3) is expressed in both proliferating and quiescent gonocytes during testis development. Cyclin D(3) expression was found in terminally differentiated Sertoli cells, in Leydig cells, and in spermatogonia in adult testis. Hence, although cyclin D(3) may control G(1)/S transition in spermatogonia, it probably has a different role in Sertoli and Leydig cells. In conclusion, the three D-type cyclins are differentially expressed during spermatogenesis. In spermatogonia, cyclins D(1) and D(3) seem to be involved in cell cycle regulation, whereas cyclin D(2) likely has a role in spermatogonial differentiation.

ATRA and KL promote differentiation toward the meiotic program of male germ cells.

“…E-MEXP-1126) shows changes in the pattern of gene expression compatible with the ongoing spermatogonial differentiation. For instance, we found upregulation of cyclin D2, previously shown to be strongly upregulated in spermatogonia of the VAD testis after administration of retinoic acid, 38 but also of early meiotic genes, such as Dzip1l, Phf7, Bmp6 and Btg4 (Table 2). At the same time, ATRA downregulates the expression of stemness genes, such as Pcgf2, Pcgf6 and Numb, and of spermatogonial markers known to be turned off at the onset of meiosis, such as Zfpm2, Pole, Egr2, Ptn, Tex16 ( Table 2).…”

Foetal germ cells: striking the balance between pluripotency and differentiation

“…For example Cyclin D3 was detected, but Cyclin D2 and the Cyclin-Cdk inhibitor, p27 Kip1 were not detected in germ cells at E14.5. By contrast Cyclin D2, Cyclin D3 and p27 Kip1 were present in quiescent germ cells at E17.5 (Beumer et al, 1999;Beumer et al, 2000). Recent work has examined the progress of germ cells into quiescence by directly examining all the members of the G1 cyclins, the CIP/KIP and INK4 inhibitors, which regulate the activity G1-S cyclin complexes, and the pocket proteins that control the check-point for G1-S phase transition.…”

Co-expressed Cyclin D variants cooperate to regulate proliferation of germline nuclei in a syncytium

“…Cyclin D regulates self-renewal in mammalian adult stem cells 41 and spermatogonial germ stem cells, 23 but is not essential for GSC proliferation in Drosophila and C. elegans. 18,19,21 The O. dioica Cyclin D variants, Da, Db, Dc and Dd are encoded by 4 different genes.…”

“…In contrast, mouse spermatogonial stem cells proliferate with a distinct G1 phase and Cyclin D plays a major role in the renewal of stem cells. 23 In comparison to other invertebrates, Cyclin D paralogs and their splice variants have been considerably amplified in O. dioica, with several exhibiting expression in the ovary. 24 Therefore, we wished to determine if the O. dioica germline exhibits a G1 phase and whether some of these Cyclin D paralogs and their splice variants have roles in regulating germline nuclear proliferation and in overcoming immediate CKIa-mediated germline cell cycle arrest during nutrient-restricted GA.…”