Canonical Wnt/β-catenin activity and differential epigenetic marks direct sexually dimorphic regulation of Irx3 and Irx5 in developing mouse gonads

Abstract

Members of the Iroquois B (IrxB) homeodomain cluster genes, specifically Irx3 and Irx5, are crucial for heart, limb and bone development. Recently, we reported their importance for oocyte and follicle survival within the developing ovary. Irx3 and Irx5 expression begins after sex determination in the ovary but remains absent in the fetal testis. Mutually antagonistic molecular signals ensure ovary versus testis differentiation with canonical Wnt/β-catenin signals paramount for promoting the ovary pathway. Notably, few direct downstream targets have been identified. We report that Wnt/βcatenin signaling directly stimulates Irx3 and Irx5 transcription in the developing ovary. Using in silico analysis of ATAC-and ChIP-Seq databases in conjunction with mouse gonad explant transfection assays, we identified TCF/LEF-binding sequences within two distal enhancers of the IrxB locus that promote β-catenin-responsive ovary expression. Meanwhile, Irx3 and Irx5 transcription is suppressed within the developing testis by the presence of H3K27me3 on these same sites. Thus, we resolved sexually dimorphic regulation of Irx3 and Irx5 via epigenetic and β-catenin transcriptional control where their ovarian presence promotes oocyte and follicle survival vital for future ovarian health.

Three-dimensional molecular architecture of mouse organogenesis

“…Interestingly, Lefty1 and Lefty2 genes were found to be specifically expressed in the male gonad, which have been reported to regulate the male germ cell fate segmentation 37 . Several genes such as Irx3 38 and Lgals7 , were identified specifically expressed in female gonad. A set of gonad-specific genes in both female and male, such as Dppa3 and Text19.1 , was also identified (Fig.…”

Identification of multiple transcription factor genes potentially involved in the development of electrosensory versus mechanosensory lateral line organs

“…Finally, Sp5 encodes a Wnt/β-catenin effector ( Kennedy et al, 2016 ), suggesting that this signalling pathway might be important for ampullary organ development. Indeed, one of the other ampullary organ-restricted genes, Irx5 , is directly upregulated by Wnt/β-catenin signalling in somatic cells of the gonad ( Koth et al, 2020 ).…”

Aicardi Syndrome Is a Genetically Heterogeneous Disorder

“…One possibility would be the participation of the implicated AIC genes in a sexually dimorphic pathway such as Wnt signalling, which has been linked to female developmental disorders in X-linked, Wnt-related genes such as DDX3X , USP9X and PORCN [ 60 , 61 , 62 ]. In mice, the Wnt signalling pathway directs sexually dimorphic autosomal gene expression in specification of ovaries and testis [ 63 ] and in the adrenal cortex, activation of Wnt signalling by Rspo1 results in adrenal cortical hyperplasia in females but cortical thinning in males [ 64 ]. We identified a WNT8B variant that affected Wnt signalling as measured using the TOPflash assay; while Shrauwen et al showed upregulation of the Wnt receptor LRP5 using RNA-Seq, and also discovered a pathogenic variant in TEAD1 [ 23 ].…”