A role for Dazl in commitment to gametogenic fate in embryonic germ cells of C57BL/6 mice

Abstract

Germ cells can be defined as the cells that undergo the terminal differentiating process of meiosis. In mice, as XX germ cells enter meiosis around Embryonic days 13.5-14.5 (E13.5-E14.5), they form meiotic figures and down-regulate pluripotency markers. XY germ cells enter proliferation arrest between E13.5 and E16.5, which is accompanied by a distinct morphological change as well. Disruption of mouse Dazl, a member of a germ-cell-specific gene family found in many metazoans, causes infertility due to germ cell loss. However the nature and timing of germ cell loss has proven variable in the mixed background mice studied thus far, and the focus has traditionally been on the postnatal spermatogenic phenotype. Here I report a role for Dazl in both XX and XY embryonic germ cell development in a C57BL/6 genetic background. I find that Dazl transcript is expressed in the XX and XY gonads starting from around E11.5. XX and XY Dazl -/- germ cells appear to arrest around E13.5 in the last cell type XX and XY germ cells share morphologically. In this, they resemble embryonic XX germ cells deficient for Stra8, a gene required for meiotic initiation.

(cont.) Between E14.5 and birth, nearly all XY Dazl -/- germ cells die by apoptosis, while the majority of XX Dazl -/- germ cells persist through birth. However, XX germ cells require Dazl to form meiotic figures, as well as to correctly express Stra8 and meiotic prophase markers SCP3, [gamma]H2AX and Dmcl. XX Dazl -/- germ cells also fail to down-regulate the pluripotency markers Oct4 and Dppa3/Stella, while XX Stra8 -/- germ cells down-regulate Oct4 normally. From this I conclude that exit from pluripotency (as represented by Oct4 loss) and entry into meiosis (as represented by Stra8 expression) are at least partially separable processes in XX embryonic germ cells, and that both require Dazl. I propose that Dazl functions at around E12.5 to allow XX germ cells to exit a pluripotent state, and to acquire competence to undergo meiosis, a fundamental capability that defines germ cells. I further speculate that Dazl is required in early embryonic XX and XY germ cells to acquire differentiation competence- including a capability to exit a pluripotent state, and respond to germ cell sex differentiation signals by entering meiosis or proliferation arrest- and hence commit to a sexually dimorphic, gametogenic fate.