Premature ovarian failure in nobox-deficient mice is caused by defects in somatic cell invasion and germ cell cyst breakdown

Abstract

Purpose To understand the mechanism of premature ovarian failure (POF). Methods The ultrastructural (electron microscopy) analysis of primordial ovarian follicles in Nobox deficient mice. Results We studied, for the first time, the fate of oogonia in embryonic (prenatal) mouse ovaries and showed that the abolishment of the transition from germ cell cysts to primordial follicles in the ovaries of Nobox deficient mice is caused by defects in germ cell cyst breakdown, leading to the formation of syncytial follicles instead of primordial follicles. Conclusions These results indicate that POF syndrome in Nobox deficient mice results from the faulty signaling between somatic and germ line components during embryonic development. In addition, the extremely unusual and abnormal presence of adherens junctions between unseparated oocytes within syncytial follicles indicates that faulty communication between somatic and germ cells is involved in, or leads to, abnormalities in the cell adhesion program.

The developmental origins of the mammalian ovarian reserve

“…Subsequent work (Rajkovic et al, 2004) discovered that Nobox is essential not only for oocyte survival, but also for the proper timing of cyst breakdown and primordial follicle assembly in the mouse. In Nobox-null mouse ovaries, defects in this process result from aberrant signaling between oocytes and somatic cells, causing impaired somatic cell invasion into cysts (Lechowska et al, 2011). Oocyte-specific gene expression is also significantly perturbed in these ovaries, with dramatic downregulation of Pouf51 (Oct4) and Sall4, among other, more widely expressed genes such as Jagged1, a NOTCH ligand .…”

“…Impaired cyst breakdown; loss of primordial follicles (Lechowska et al, 2011;Rajkovic et al, 2004;Suzumori et al, 2002) TBP-associated Factor 4b (Taf4b) Impaired cyst breakdown; loss of primordial follicles (Falender et al, 2005;Freiman et al, 2001;Grive et al, 2014;Lovasco et al, 2010;Voronina et al, 2007) …”

Genomic Markers of Ovarian Reserve

“…27 Nobox has been shown to promote oocyte and follicle growth beyond the primordial follicle stage. 28 Germ cell cyst breakdown and oocyte separation is impeded in Nobox knockout mice and loss of Nobox leads to an accelerated loss of oocytes 28,29 (Fig. 1A).…”

Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing

“…Female Nobox −/− KO mice have displayed a dramatic postnatal reduction of oocyte number secondary to meiosis dysfunction in oogonia and impaired primordial to primary follicle transition (Rajkovic et al, 2004). Electron microscopy has revealed an increase in adherens junctions between unseparated oocytes within syncytial follicles when assessing KO animals' ovaries, which might have been related to cell adhesion dysfunction (Lechowska et al, 2011). Moreover, these experiments led to proposing that the infertile phenotype of female Nobox null mice might be associated with abnormal signalling between germ and somatic cells.…”