Altered germline cyst and oocyte differentiation inTex14mutant mice reveal a new mechanism underlying female reproductive life-span

Abstract

In adult mammalian females, primordial follicles that form in the fetal/neonatal ovary are the only source to sustain adult ovarian function. Our previous studies revealed that during oocyte differentiation and primordial follicle formation in mouse fetal ovaries, primary oocytes form via gaining cytoplasm and organelles from sister germ cells that are connected to them by intercellular bridges within germline cysts. To better understand the role of intercellular bridges in oocyte differentiation, we analyzed mutant females lacking testis-expressed 14 (Tex14), a gene involved in cytokinesis and bridge formation. In Tex14 -/fetal ovaries, germ cells divide to form a reduced number of cysts in which sister germ cells are still connected via syncytia or fragmented cell membranes, rather than normal intercellular bridges. Compared with wildtype cysts, Tex14 -/cysts fragment at a higher frequency and produce a greatly reduced number of primary oocytes with highly precocious cytoplasmic enrichment and enlarged volume. By contrast, Tex14 +/germline cysts are less fragmented and generate primary oocytes that are smaller than wild type. Interestingly, enlarged Tex14 -/primary oocytes are much more stable than wild type oocytes and more efficiently sustain folliculogenesis, whereas undersized Tex14 +/primary oocytes turn over at an accelerated rate. Our observations directly link the nature of fetal germ cell connectivity to cytoplasmic enrichment during oocyte differentiation and to oocyte developmental potential in the adult ovary. Our results imply that the duration of adult ovarian function is strongly influenced by the number of primary oocytes acquiring highly enriched cytoplasm during oocyte differentiation in fetal ovaries, rather than just by the size of the primordial follicle pool.

Intercellular bridges coordinate the transition from pluripotency to meiosis in mouse fetal oocytes

“…4 ). A likely interpretation is that the concurrent or subsequent membrane fragmentation described in Tex14 −/− germ cells by Nuzhat et al ( 37 ) does not enable sharing of cytoplasmic contents. Our approach involved drug-induced recombination-based labeling of a subset of germ cells to distinguish individual clones in the ovary.…”

“…By contrast, in female germ cells, ICBs exist more transiently during fetal development; Tex14 mice have fewer oocytes starting from postnatal development and bear fewer litters (14). A recent study of Tex14 mutants finds elevated apoptosis and decreased numbers of female germ cells starting at E12.5 (37); although we did not observe a parallel decrease in germ cell numbers, it is noteworthy that we maintain Tex14 −/− mice on a mixed genetic background rather than pure C57BL/6. Membrane connections between germ cells in Tex14 −/− ovaries were observed in the prior study by ultrastructure at E14.5 (37); however, our extensive analysis of Rainbow multicolored germ cells labeled from E10.5 to E13.5 did not reveal any clones bearing two fluorophores in Tex14 as occurs in WT (Fig.…”

The Beginning of Meiosis in Mammalian Female Germ Cells: A Never-Ending Story of Intrinsic and Extrinsic Factors

“…The mechanisms that drive the breakdown of cysts and lead to the formation of primordial follicles are not known in detail. However, it is known that TEX14 is required for the formation, maintenance, and/or stability of the intercellular bridge both in male and female germ cells [ 180 ]. Recent results suggested a model alternative to the metabolic stress by which germ-cell nests could regulate the timing of meiotic entry across the ovary.…”

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

“…Progesterone, produced by follicular granulosa cells and corpora lutea, is critical for successful oocyte maturation and ovulation 55,56 . Communication among germ cells also takes place through intercellular bridges that connect the cytoplasm of adjacent cells into a syncytium; males that cannot form these bridges (such as Tex14 knockouts) are sterile 57 (these structures are important, but not essential, for female fertility 58,59 ). These germ cell bridges/syncytia have been proposed to foster dosage compensation in haploid cells, coordination of meiotic entry, and sharing of signals for synchronous cell divisions within seminiferous tubules 57,58,60 .…”