IRX3 and IRX5 collaborate during ovary development and follicle formation to establish responsive granulosa cells in the adult mouse†

Abstract

Healthy development of ovarian follicles depends on appropriate interactions and function between oocytes and their surrounding granulosa cells. Previously, we showed that double knockout of Irx3 and Irx5 (Irx3/5 DKO) in mice resulted in abnormal follicle morphology and follicle death. Further, female mouse models of individual Irx3 or Irx5 knockouts were both subfertile but with distinct defects. Notably, the expression profile of each gene suggests independent roles for each, first they are colocalized in pre-granulosa cells during development that then progresses to include oocyte expression during germline nest breakdown and primordial follicle formation. Thereafter, their expression patterns diverge between oocytes and granulosa cells coinciding with the formulation and maturation of intimate oocyte-granulosa cell interactions. The objective of this study was to investigate the contributions of Irx5 and somatic cell-specific expression of Irx3 during ovarian development. Our results show that Irx3 and Irx5 contribute to female fertility through different mechanisms and that Irx3 expression in somatic cells is important for oocyte quality and survival. Based on evaluation of a series of genetically modified mouse models, we conclude that IRX3 and IRX5 collaborate in the same cells and then in neighboring cells to foster a healthy and responsive follicle. Long after these two factors have extinguished, their legacy enables these intercellular connections to mature and respond to extracellular signals to promote follicle maturation and ovulation.

Single-Cell Atlas of the Chinese Tongue Sole (Cynoglossus semilaevis) Ovary Reveals Transcriptional Programs of Oogenesis in Fish

“…In contrast, krt18 , a marker gene of pre-granulosa cells and mural granulosa cells in human ovary ( Fan et al, 2019 ), was expressed in GC3. Additionally, GC3 showed specific high activity of TFs related to pre-granulosa cells, such as lhx9 , wt1, and irx3 ( Fu et al, 2020 ; Knarston et al, 2020 ) . Accordingly, GC3 might be pre-granulosa cells surrounding early follicles.…”

FOXL2 interaction with different binding partners regulates the dynamics of ovarian development

“…S1D, marked with an asterisk) ( 39 ); Star , which encodes steroidogenic acute regulatory protein ( 42 ); and Cyp17a1 . In addition, the 1W-8W cluster included sex differentiation genes such as Wt1 ( 43 ), Esr1 ( 44 ), Irx3 ( 45 ), and Wnt4 ( 33 ), as well as Sertoli-specific genes, such as Sox9 ( 36 ), Inha ( 46 ), and Fndc3a ( 47 ). Last, the E14.5-8W cluster was enriched for DNA repair pathways, a recently discovered function of FOXL2 ( 48 ) and included genes such as Ddx1 , Ruvbl1 , and Exo5 .…”

FOXL2 interaction with different binding partners regulates the dynamics of ovarian development

“…Whilst the timepoints E14.5-1W shared several targets involved in urogenital development, the group of genes bound by FOXL2 between 1W and 8W featured genes encoding for members of the steroidogenesis pathway, including the known FOXL2 targets Esr2, for which we detected binding in the functional enhancer "Peak 3", located in one intronic region as previously demonstrated [27] (Figure 1E), the human steroidogenic acute regulatory Star gene [44] and Cyp17a1. Additionally, sex differentiation genes were stably bound by FOXL2 between 1W and 8W, and these include granulosa-specific genes such as Esr1 [45], Irx3 [46] and Wnt4 [34], as well as Sertoli-specific genes, such as Sox9 [37], Inha [47], Fndc3a [48] and bivalent factors such as Wt1 [49]. Additionally, we found binding within the cell-cycle repressor gene Cdkn1b, a known FOXL2 target gene that regulates granulosa cell proliferation (Figure 2 and Figure S2B) [30].…”