Mitotic Arrest in Teratoma Susceptible Fetal Male Germ Cells

Abstract

Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27KIP1, p15INK4B, activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility.

Prostaglandin D2 acts through the Dp2 receptor to influence male germ cell differentiation in the foetal mouse testis

“…The different percentages of EdU-positive germ cells compared with those obtained with E13.5 L/H-Pgds −/− testes (Fig. 1D) were probably due to the different genetic backgrounds, namely CD1 (CAY experiments) and C57BL/6 (L/H-Pgds −/− ) (Western et al, 2011). This effect on proliferation was specific to the Dp2 receptor, as oral administration of the Dp1 antagonist BWA868C did not significantly modify the number of proliferating germ cells, whereas the Dp2 agonist 15R-PGD 2 potentiated the effect of endogenous PGD 2 (supplementary material Fig.…”

Testicular teratomas: an intersection of pluripotency, differentiation and cancer biology

“…At E12.5 greater than 60% of germ cells can be found in S or G2/M phases of the cell cycle. By E14.5 80% or more of germ cells are in G1/G0 in 129T2, CD-1, and C57BL/6 mice (Western et al, 2011). Mitotic arrest in G0 likely involves regulation of the G1/S checkpoint (Fig.…”

“…Here we will focus on the differentiation of male gonadal germ cells, which are incorporated into the testis cords, the nascent seminiferous tubules. Shortly thereafter, male germ cells enter mitotic arrest in G0, which persists until after birth (Western et al, 2011). The window of time in which Stevens found transplanted 129/Sv PGCs to be prone to transformation to teratoma is bracketed by PGC arrival at the gonad and their arrest in G0 of the cell cycle ( Fig.…”

“…The role of these transcription factors in PGCs is incompletely understood, but they are likely to be involved in the suppression of somatic differentiation as the germ cells undergo epigenetic reprogramming. Expression of all three genes persists until after PGCs initiate sex-specific differentiation in the gonads (Western et al, 2011, Yamaguchi et al, 2005.…”

“…A close look at the expression of these factors, both at the transcript and protein level, showed an initial increase in negative cell cycle regulators p27 and p15 along with a decrease in Cyclin E expression at E13.5. Activation of retinoblastoma protein (pRB), which also occurs at this stage, was proposed to be critical to arrest at the G1/S checkpoint (Sorrentino et al, 2007, Western et al, 2008, Western et al, 2011. However, a null mutation in pRB had a modest effect, where most germ cells still entered mitotic arrest even in the absence of pRB (Spiller et al, 2010).…”