Abstract
Fetal germ cell development is tightly regulated by the somatic cell environment, and is characterised by cell cycle states that differ between XY and XX gonads. In the testis, gonocytes enter G1/G0 arrest from 12.5 days post coitum (dpc) in mice and maintain cell cycle arrest until after birth. Failure to correctly maintain G1/G0 arrest can result in loss of germ cells or, conversely, germ cell tumours. High mobility group box containing transcription factor 1 (HBP1) is a transcription factor that was previously identified in fetal male germ cells at the time of embryonic cell cycle arrest. In somatic cells, HBP1 is classified as a tumour suppressor protein, known to regulate proliferation and senescence. We therefore investigated the possible role of HBP1 in the initiation and maintenance of fetal germ cell G1/G0 arrest using the mouse model. We identified two splice variants of Hbp1, both of which are expressed in XY and XX fetal gonads, but only one of which is localised to the nucleus in in vitro assays. To investigate Hbp1 loss of function, we used embryonic stem (ES) cells carrying a Genetrap mutation for Hbp1 to generate mice lacking Hbp1 function. We found that Hbp1-genetrap mouse mutant germ cells proliferated correctly throughout development, and adult males were viable and fertile. Multiple Hbp1-LacZ reporter mouse lines were generated, unexpectedly revealing Hbp1 embryonic expression in hair follicles, eye and limbs. Lastly, in a model of defective germ cell G1/G0 arrest, the Rb1-knockout model, we found no evidence for Hbp1 mis-regulation, suggesting that the reported RB1-HBP1 interaction is not critical in the germline, despite co-expression.
Highlights
Germ cells are highly specialized cells that are uniquely capable of undergoing meiosis and represent our means to reproduce
We investigated the expression of both transcripts in developing mouse gonads at 14.5 dpc using whole mount in situ hybridization (ISH)
The embryonic differentiation of XX and XY germ cells diverges at 12.5 dpc with XX germ cell entry into the first phase of meiosis and XY germ cell entry into G1/G0 arrest [1]
Summary
Germ cells are highly specialized cells that are uniquely capable of undergoing meiosis and represent our means to reproduce. HBP1 Knockout Is Viable and Fertile germ cells enter G1/G0 arrest, signifying commitment to spermatogenesis [1], while entry into meiosis prophase I in the ovary signifies commitment to oogenesis [2]. Retinoic acid has been shown to modulate meiosis entry in the ovary, while being antagonistic to pro-spermatogonia development [3,4,5]. Failure of this process to occur correctly has been linked to testicular germ cell tumours and their precursor, germ cell neoplasia in situ [6, 7]. This connection provides strong motivation for investigating cell cycle regulation in these specialised cells
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