CDC14B role in male meiosis (#51)
The cell cycle is driven by the sequential activation and destruction of cyclins and their interaction with cyclin-dependent-kinases (CDK’s). The anaphase-promoting complex or cyclosome (APC/C) triggers the degradation of multiple mitotic substrates, and it is activated through association with either cdc20/Fizzy or cdh1/fizzy-related, which also confers substrate specificity to the complex. Fizzy-related 1 (Fzr1) protein is present in all somatic cells, and is also abundant and active in mammalian oocytes, acting in the meiotic prophase I arrest maintenance, and in the proper chromosome division during meiosis I.1 However, APC/CFzr1 function in male meiosis remains to be elucidated.
A Fzr1 germ cell-deficient mouse model was generated through Cre-loxP technology in order to study the function of Fzr1 in mammalian spermatogenesis. The Fzr1-null mice are infertile, displaying germ cell arrest at early stages of spermatogenesis, and thus lacking spermatozoa. The Cdc14b-Fzr1-Plk axis is a well-established mechanism of DNA damage response during G2 stage, and conserved from yeast to human. Phosphatase Cdc14b regulates Fzr1 activity by dephosphorylating, and consequently activating Fzr1 leading to the degradation of several APC/CFzr1 substrates (e.g. cyclin B and Plk1).2 Cdc14b protein levels are increased in the Fzr1-null mice testes, while significantly reduced at the mRNA level. Additionally, a clear interaction between Cdc14b and Fzr1 was observed through PLA assay in meiotic spermatocyte cells.
Thus, these results showed that loss of Fzr1 compromised the normal mouse spermatogenesis, and induced DNA-damage responses, namely through Cdc14b accumulation and down-regulation. Cdc14b is therefore, a newly described target of Fzr1 in mouse spermatogonia / sperm germ cells.
- Reis, A., Chang, H.Y., Levasseur, M. & Jones, K.T., 2006, APCcdh1 activity in mouse oocytes prevents entry into the first meiotic division, Nature cell biology, 8(5), pp. 539-40
- Hu, D., Qiao, X., Wu, G. & Wan, Y., 2011, The emerging role of APC/CCdh1 in development, Seminars in cell & developmental biology, 22(6), pp. 579-8