Scaffold Subunit Aalpha of PP2A Is Essential for Female Meiosis and Fertility in Mice1

Abstract

Ppp2r1a encodes the scaffold subunit Aalpha of protein phosphatase 2A (PP2A), which is an important and ubiquitously expressed serine threonine phosphatase family and plays a critical role in many fundamental cellular processes. To identify the physiological role of PP2A in female germ cell meiosis, we selectively disrupted Ppp2r1a expression in oocytes by using the Cre-Loxp conditional knockout system. Here we report for the first time that oocyte-specific deletion of Ppp2r1a led to severe female subfertility without affecting follicle survival, growth, and ovulation. PP2A-Aalpha was essential for regulating oocyte meiotic maturation because depletion of PP2A-Aalpha facilitated germinal vesicle breakdown, causing elongation of the MII spindle and precocious separation of sister chromatids. The resulting eggs had high risk of aneuploidy, though they could be fertilized, leading to defective embryonic development and thus subfertility. Our findings provide strong evidence that PP2A-Aalpha within the oocyte plays an indispensable role in oocyte meiotic maturation, though it is dispensable for folliculogenesis in the mouse ovary.

PP2A regulates kinetochore-microtubule attachment during meiosis I in oocyte

“…45 The loss of scaffold subunit PP2A-Aa in mouse oocytes compromised spindle shape and cytokinesis in meiosis II without affecting spindle formation during meiosis I. 24 Comparing with our results, the scaffold and catalytic subunits of PP2A appear to play different specific roles during meiotic maturation. Another possibility is that PP2A-Ab functionally compensates for PP2A-Aa during oocyte meiosis I.…”

“…Previous studies showed that inhibition of PP2A by OA or specifically deleting scaffold PP2A-Aa facilitates GVBD in oocytes, 19,24,37,38 and PP2Acb may play a key role in the meiotic arrest of oocytes. 18,19 In our study, the loss of PP2Acs did not significantly affect GVBD kinetics in oocytes under normal culture condition.…”

“…Moreover, spindles elongated more in DKO oocytes (Supplementary information, Figure S3B), in agreement with previous studies. 21,24 Note that at GVBD 8 h and GVBD 16 h, chromosomes were aligned in 1.1% and 8.6% of the DKO oocytes, respectively. These DKO oocytes may correspond to the DKO oocytes with unstably aligned chromosomes that were observed in the live microscopy experiments (Fig.…”

“…DKO females had normal ovary morphology and ovulation, indicating that oocyte specific loss of PP2A activity has few effects on follicular development, in agreement with a previous study in which PP2A-Aa were deleted specifically in mouse oocytes. 24 …”

“…Using genetically modified mouse model to study the in vivo roles of PP2A could provide more reliable evidence. 24 The risk of trisomic pregnancies increases with female age, the vast majority of human aneuploidies, such as Down's syndrome, result from segregation errors in female meiosis I. 25 Meiosis I in oocytes can be disrupted by OA treatment but the regulation of PP2A in dynamic spindle assembly and chromosome alignment during this stage, are not clear.…”