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Women and other mammalian females are born with a finite supply of oocytes that determine their reproductive lifespan. During fetal development, individual oocytes are enclosed by a protective layer of granulosa cells to form primordial follicles that will grow, mature, and eventually release the oocyte for potential fertilization. Despite the knowledge that follicles are dysfunctional and will die without granulosa cell-oocyte interactions, the mechanisms by which these cells establish communication is unknown. We previously identified that two members of the Iroquois homeobox transcription factor gene family,  Irx3  and  Irx5 , are expressed within developing ovaries but not testes. Deletion of both factors ( Irx3   -   Irx5   EGFP  / Irx3   -   Irx5   EGFP  ) disrupted granulosa cell-oocyte contact during early follicle development leading to oocyte death. Thus, we hypothesized that  Irx3  and  Irx5  are required to develop cell-cell communication networks to maintain follicle integrity and female fertility. A series of  Irx3  and  Irx5  mutant mouse models were generated to assess roles for each factor. While both  Irx3  and  Irx5  single mutant females were subfertile, their breeding outcomes and ovary histology indicated distinct causes. Careful analysis of  Irx3 - and  Irx5 -reporter mice linked the cause of this disparity to dynamic spatio-temporal changes in their expression patterns. Both factors marked the progenitor pre-granulosa cell population in fetal ovaries. At the critical phase of germline nest breakdown and primordial follicle formation however,  Irx3  and  Irx5  transitioned to oocyte- and granulosa cell-specific expression respectively. Further investigation into the cause of follicle death in  Irx3   -   Irx5   EGFP  / Irx3   -   Irx5   EGFP   ovaries uncovered specific defects in both granulosa cells and oocytes. Granulosa cell defects included poor contributions to basement membrane deposition and mis-localization of gap junction proteins. Granulosa cells and oocytes both presented fewer cell projections resulting in compromised cell-cell communication. Altogether, we conclude that  Irx3  and  Irx5  first work together to define the pregranulosa cell population of germline nests. During primordial follicle formation, they transition to oocyte- and granulosa cell-specific expression patterns where they cooperate in neighboring cells to build the foundation for follicle integrity. This foundation is left as their legacy of the essential oocyte-granulosa cell communication network that ensures and ultimately optimizes the integrity of the ovarian reserve and therefore, the female reproductive lifespan.

plos genetics

Dynamic expression patterns of Irx3 and Irx5 during germline nest breakdown and primordial follicle formation promote follicle survival in mouse ovaries