Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53‐dependent and results in female sterility

Abstract

Murine double minute 2 and 4 (Mdm2, Mdm4) are major p53-negative regulators, preventing thus uncontrolled apoptosis induction in numerous cell types, although their function in the female germ line has received little attention. In the present work, we have generated mice with specific invalidation of Mdm2 and Mdm4 genes in the mouse oocyte (Mdm2 Ocko and Mdm4Ocko mice), to test their implication in survival of these germ cells. Most of the Mdm2 Ocko but not Mdm4 Ocko mice were sterile, with a dramatic reduction of the weight of ovaries and genital tract, a strong increase in follicle-stimulating hormone and luteinizing hormone serum levels, and a reduction of anti-mullerian hormone serum levels. Histological analyses revealed an obvious decrease of the number of growing follicles beyond the primary stage in Mdm2 Ocko ovaries in comparison to controls, with a pronounced increase in the apparition of primary atretic follicles, most being devoid of oocyte. Similar phenotypes were observed with Mdm2 Ocko Mdm4Ocko ovaries, with no worsening of the phenotype. However, we failed to detect any increase in p53 level in mutant oocytes, nor any other apoptotic marker, introgression of this targeted invalidation in p53À/À mice restored the fertility of females. This study is the first to show that Mdm2, but not Mdm4, has a critical role in oocyte survival and would be involved in premature ovarian insufficiency phenotype.

Mdm2‐p53‐SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality

“…that oocyte-specific Mdm2 deficiency increases atretic follicles and impairs oocyte survival and folliculogenesis through p53, resembling premature ovarian failure in phenotypes (47). In contrast, our study demonstrated that granulosa cell-specific deletion of Mdm2 impaired oocyte maturation, ovulation, and fertilization through p53 induction in the periovulatory phase, suggesting that the Mdm2-p53 pathway critically affects ovarian functions in cell-specific and developmental stage-specific manners.…”

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Several studies have recently shown that MDM2 is associated with rheumatoid arthritis (RA), an autoimmune disorder that causes chronic inflammation and injury of the joints and other organs in the body and the major findings are summarized in Figure . For instance, Assmann et al have examined the roles of two functional single nucleotide polymorphisms (SNPs), MDM2 SNP309 and p53 P72R, in patients who fulfill the American College of Rheumatology criteria for RA.…”

“…Fouchécourt et al and Livera et al have recently reported that the MDM2‐p53 pathway is implicated in male and female fertility, respectively (Table ) . Their studies have demonstrated that MDM2 protects Sertoli cells and oocytes from p53‐mediated apoptosis, while MDM2 inhibition causes male and female sterility by activating p53 and inducing p53‐dependent apoptosis of Sertoli cells and oocytes . However, these studies were preliminary, and more studies are needed to determine the relevance of MDM2 to human fertility.…”

“…Although its roles in malignancy and tumor progression have been the focus of most previous research, MDM2 has recently received increasing attention for its noncarcinogenic roles in various disorders and conditions, including inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure (HF) and cardiovascular diseases, nephropathy, diabetes, obesity, and fertility . As illustrated in Figure , MDM2 exerts its activity in both malignant and nonmalignant diseases by directly regulating diverse targets, for example, p53, p21, NFκB, and microtubule‐associated protein kinase (MAPK).…”

Mdm proteins: critical regulators of embryogenesis and homoeostasis

“…To determine whether Mdm2 and Mdm4 are implicated in the survival of oocytes during their development, a Cre gene driven by the Zona Pellucida Glycoprotein 3 promoter ( Zp3-Cre ), which is exclusively expressed in growing oocytes, is used in conjunction with the conditional Mdm2 FM and Mdm4 FX alleles (de Vries et al, 2000; Livera et al, 2016). Loss of Mdm2 in the oocytes ( Mdm2 FM/− Zp3-Cre ) leads to significantly decreased fertility, irregular menstrual cycling, and small ovaries.…”