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. 2020 Jul;19(13):1654-1664.
doi: 10.1080/15384101.2020.1762314. Epub 2020 May 18.

Cyclin A2 is essential for mouse gonocyte maturation

Fanhua Ma  1   2 , Xiangyuan Wang  2 , Sanny S W Chung  2 , Piotr Sicinski  3 , Enyuan Shang  4 , Debra J Wolgemuth  2   5
Affiliations

Cyclin A2 is essential for mouse gonocyte maturation

Fanhua Ma et al. Cell Cycle. 2020 Jul.

Abstract

In mammals, male gonocytes are derived from primordial germ cells during embryogenesis, enter a period of mitotic proliferation, and then become quiescent until birth. After birth, the gonocytes proliferate and migrate from the center of testicular cord toward the basement membrane to form the pool of spermatogonial stem cells (SSCs) and establish the SSC niche architecture. However, the molecular mechanisms underlying gonocyte proliferation, migration and differentiation are largely unknown. Cyclin A2 is a key component of the cell cycle and required for cell proliferation. Here, we show that cyclin A2 is required in mouse male gonocyte development and the establishment of spermatogenesis in the neonatal testis. Loss of cyclin A2 function in embryonic gonocytes by targeted gene disruption affected the regulation of the male gonocytes to SSC transition, resulting in the disruption of SSC pool formation, imbalance between SSC self-renewal and differentiation, and severely abnormal spermatogenesis in the adult testis.

Keywords: Cyclin A2; gonocyte differentiation; spermatogonial stem cells.

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Conflict of interest statement

The authors declare there are no conflicts of interest.

Figures

Figure 1.
Figure 1.
Cyclin A2 protein is expressed in mouse gonocytes. Immunohistochemistry with anti-cyclin A2 antibodies at pnd 0.5, pnd 1.5, pnd 2.5, and pnd 3.5 testes showed that gonocytes express cyclin A2 from pnd 1.5 but not at pnd 0.5; the yellow arrowheads in pnd 1.5, 2.5, and 3.5 indicate cyclin A2 positive gonocytes. Bar indicates 50 μm.
Figure 2.
Figure 2.
Loss of cyclin A2 expression in gonocytes results in severely abnormal spermatogenesis and few if any germ cells in the adult testis. (a,b) Testicular sections from control and A2CKOgono at pnd 1.5 were stained with anti-cyclin A2 antibody using immunohistochemistry. The yellow arrows indicate cyclin A2 positive germ cells and red arrows indicate the cyclin A2 negative germ cells. Bar indicates 50 μm. (c,d) H&E staining in adult mouse testes from control (c) and A2CKOgono (d). The black lines indicate the hypertrophy of the interstitial tissue. Bar indicates 200 μm. The asterisks indicate the vacuolation of the tubules.
Figure 3.
Figure 3.
The number of germ cells decreased in A2CKOgono compared with controls as early as pnd 2.5. (a) Paraffin-embedded testis sections from A2CKOgono and control mice were co-stained with anti-Vasa antibody and anti-Gata4 antibody and germ cell numbers per tubule quantified at pnd 7.5 (126 tubules from 2 mice were counted in A2CKOgono testis, 88 tubules from 2 mice in control); pnd 4.5 (195 tubules from 2 mice in A2CKOgono, 143 tubules from 2 mice in control); pnd 3.5 (224 tubules from 3 mice in A2CKOgono, 107 tubules from 3 mice in control); and pnd 2.5 (108 tubules from 3 mice in A2CKOgono, 97 tubules from 3 mice in control). Bar indicates 50 μm. (b) Quantitative analysis depicting the number of Vasa-positive cells per tubule (y axis) in A2CKOgono and control from pnd 7.5 to pnd 2.5 (x axis). Data represent Mean ± SEM. * P < 0.05; **P < 0.001.
Figure 4.
Figure 4.
The number of gonocytes in A2CKOgono is decreased compared with control in pnd 1.5 to 4.5 but their location is not affected. (a) Schematic of location of germ cells in seminiferous tubules in pnd 1.5 and pnd 4.5 testes: red ovals indicate Sertoli cells; light green indicates the germ cells located in the central compartment; dark green indicates a germ cell located in the basal compartment, touching the basement membrane; (b) The number of germ cells located at either basal or central region of the testicular cords was quantified in A2CKOgono and controls from pnd 2.5 (n = 3), 3.5 (n = 3), and 4.5 (n = 3); (c, d) The percentage of the total germ cells located at the central (% Ncentral cells) or basal (% Nbasal cells) regions of testicular tubules in A2CKOgono and control (y axis) from pnd2.5 to pnd4.5 (x axis). Data represent Mean ± SEM. * P < 0.05, ** P < 0.001.
Figure 5.
Figure 5.
Sub-cellular localization of Foxo1 in A2CKOgono and controls to indicate transition from gonocytes to SSC. (a) Paraffin-embedded testis sections from A2CKOgono and control at pnd 4.5 were stained with anti-Foxo1 antibody. Bar indicates 50 μm. Red arrowheads indicate the cytoplasmic Foxo1-positive cells; yellow arrows indicate nuclear Foxo1-positive cells. (b) Quantitative analysis of nuclear versus cytoplasmic Foxo1-positive cells per tubule and (c) the percentage of nuclear versus cytoplasmic Foxo1-positive cells in A2CKOgono (n = 158 tubules from three mice) and controls (n = 186 tubules from three mice. Data represent Mean ± SEM. *P < 0.05, **P < 0.001.
Figure 6.
Figure 6.
Cartoon depicting the possible molecular mechanism of cyclin A2 function in the gonocyte-SSC transition. In this model, cyclin A2 directly regulates Akt activation in a phosphorylation–dependent manner and activated Akt regulates the localization of Foxo1 through phosphorylation.
See this image and copyright information in PMC

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