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Key Event Title
Premature initiation of meiosis in fetal male germ cells
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Ectopic ATRA in fetal testis leads to reduced spem count||KeyEvent||Terje Svingen (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Male germ cell fate, fetal life
In male mammals, the XY germ cells initially proliferate during early stages of fetal testis differentiation, then enter a stage of mitotic arrest. Once in this G0/G1 cell cycle phase, the germ cells gradually stop expressing several pluripotency markers and start expressing genes considered characteristic of male germ cell differentiation (Spiller & Bowles, 2019). The mitotically arrested germ cells, now referred to as pro-spermatogonia (McCarrey, 2013), remain quiescent until after birth (McLaren, 1984).
Premature meiosis as Key Event
Germ cells in developing testis enter cell cycle quiescence during fetal life; i.e. they must avoid entering meiosis as germ cells do in the fetal ovary. In the ovaries, germ cell meiosis is initiated by the presence of all-trans retinoic acid (atRA) which induces expression of key pre-meiotic gene Stra8 (Bowles et al, 2006; Koubova et al, 2006). In the testes, atRA is degraded by the CYP26B1 enzyme, and therefore germ cells do not express Stra8 and do not enter meiosis (Bowles et al, 2006; Koubova et al, 2006; MacLean et al, 2007; Spiller et al, 2017; Trautmann et al, 2008). It is not yet clear how atRA concentrations are controlled in the human fetal testis. Regardless, there is evidence that the presence of atRA during human fetal testis development is detrimental to germ cell development (Jørgensen et al, 2015).
How It Is Measured or Detected
There are no OECD validated assays for measuring meiotic initiation.
Meiotic factors, such as Stra8, Sycp3, gH2AX mRNA and protein levels can be measured using various probes and antibodies that are commercially available eg. (Bowles et al, 2006).
Indirect measurements in animal models can be performed using the Stra8 promoter element driving expression of reporter protein GFP (Feng et al, 2021). This reporter assay can detect the presence (GFP) or absence (GFP negative) of Stra8 induction in a semi-quantitative manner.
Domain of Applicability
Fetal male germ cells must enter cell cycle quiescence (G0/G1 arrest) during fetal life and premature meiosis in gonocytes leads to their removal/death (Spiller et al, 2017). This process is conserved between mice, rats and humans.
Bowles J, Feng CW, Spiller CM, Davidson TL, Jackson A, Koopman P (2010) FGF9 suppresses meiosis and promotes male germ cell fate in mice. Dev Cell 19: 440-449
Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P (2006) Retinoid signaling determines germ cell fate in mice. Science 312: 596-600
Feng CW, Burnet G, Spiller CM, Cheung FKM, Chawengsaksophak K, Koopman P, Bowles J (2021) Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. Development 148: dev194977
Jørgensen A, Nielsen JE, Perlman S, Lundvall L, Mitchell RT, Juul A, Rajpert-De Meyts E (2015) Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development. Hum Reprod 30: 2351-2363
Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC (2006) Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A 103: 2474-2479
MacLean G, Li H, Metzger D, Chambon P, Petkovich M (2007) Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology 148: 4560-4567
McCarrey JR (2013) Toward a more precise and informative nomenclature describing fetal and neonatal male germ cells in rodents. Biol Reprod 89: 47
McLaren A (1984) Meiosis and differentiation of mouse germ cells. Symp Soc Exp Biol 38: 7-23
Spiller C, Bowles J (2019) Sexually dimorphic germ cell identity in mammals. Curr Top Dev Biol 134: 252-288
Spiller C, Koopman P, Bowles J (2017) Sex Determination in the Mammalian Germline. Annu Rev Genet 51: 265-285
Trautmann E, Guerquin MJ, Duquenne C, Lahaye JB, Habert R, Livera G (2008) Retinoic acid prevents germ cell mitotic arrest in mouse fetal testes. Cell Cycle 7: 656-664