FOXL2 transcriptionally represses<i>Sf1</i>expression by antagonizing WT1 during ovarian development in mice

Takasawa, Kei; Kashimada, Kenichi; Pelosi, Emanuele; Takagi, Motoki; Morio, Tomohiro; Asahara, Hiroshi; Schlessinger, David; Mizutani, Shuki; Koopman, Peter

doi:10.1096/fj.13-246108

Cited by 45 publications

(32 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wt1 vivo -morpholino treatment, initiated at the same developmental stage also revealed specific effects of WT1 in embryonic ovaries as exemplified by the reduction of Dax1 and Foxl2 mRNA levels (Fig 4B). It has recently been reported that FOXL2 antagonizes the stimulatory effect of WT1(-KTS) on Nr5a1 expression by interacting with the proximal Nr5a1 promoter region [47]. Our data provide evidence that WT1 also interferes with the transcriptional network controlling ovarian development.…”

Section: Discussionsupporting

confidence: 56%

Ex vivo cultures combined with vivo-morpholino induced gene knockdown provide a system to assess the role of WT1 and GATA4 during gonad differentiation

et al. 2017

View full text Add to dashboard Cite

Gonad morphogenesis relies on the correct spatiotemporal expression of a number of genes that together fulfill the differentiation of the bipotential gonad into testes or ovaries. As such, the transcription factors WT1 and GATA4 are pivotal for proper gonadal development. Here we address the contributions of GATA4 and WT1 to the sex differentiation phase in testes and ovaries. We applied an ex vivo technique for cultivating gonads in hanging droplets of media that were supplemented with vivo-morpholinos to knockdown WT1 and GATA4 either alone or in combination at the same developmental stage. We show that WT1 is equally important for both, the initial establishment and the maintenance of the sex-specific gene expression signature in testes and ovaries. We further identified Foxl2 as a novel putative downstream target gene of WT1. Moreover, knockdown of WT1 reduced mRNA levels of several molecular components of the hedgehog signaling pathway in XY gonads, whereas Gata4 vivo-morpholino treatment increased transcripts of Dhh and Ptch1 in embryonic testes. The data suggest that for its proper function, WT1 relies on the correct expression of the GATA4 protein. Furthermore, GATA4 down-regulates several ovarian promoting genes in testes, such as Ctnnb1, Fst, and Bmp2, suggesting that this repression is required for maintaining the male phenotype. In conclusion, this study provides novel insights into the role of WT1 and GATA4 during the sex differentiation phase and represents an approach that can be applied to assess other proteins with as yet unknown functions during gonadal development.

show abstract

Section: Discussionsupporting

confidence: 56%

Ex vivo cultures combined with vivo-morpholino induced gene knockdown provide a system to assess the role of WT1 and GATA4 during gonad differentiation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…It has been reported that Sf1 is required for the development of steroidogenic cells and that loss of Sf1 results in agenesis of gonads and adrenal glands (Luo et al, 1994;Sadovsky et al, 1995). The relationship between Wt1 and Sf1 has been studied previously using TM3 (Takasawa et al, 2014), TM4 (Wilhelm and Englert, 2002) and C2C12 (Val et al, 2007) cell lines. These results suggest that the expression of Sf1 was activated by WT1.…”

Section: Discussionmentioning

confidence: 99%

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

et al. 2016

View full text Add to dashboard Cite

Supporting cells (Sertoli and granulosa) and steroidogenic cells (Leydig and theca-interstitium) are two major somatic cell types in mammalian gonads, but the mechanisms that control their differentiation during gonad development remain elusive. In this study, we found that deletion of Wt1 in the ovary after sex determination caused ectopic development of steroidogenic cells at the embryonic stage. Furthermore, differentiation of both Sertoli and granulosa cells was blocked when Wt1 was deleted before sex determination and most genital ridge somatic cells differentiated into steroidogenic cells in both male and female gonads. Further studies revealed that WT1 repressed Sf1 expression by directly binding to the Sf1 promoter region, and the repressive function was completely abolished when WT1 binding sites were mutated. This study demonstrates that Wt1 is required for the lineage specification of both Sertoli and granulosa cells by repressing Sf1 expression. Without Wt1, the expression of Sf1 was upregulated and the somatic cells differentiated into steroidogenic cells instead of supporting cells. Our study uncovers a novel mechanism of somatic cell differentiation during gonad development.

show abstract

“…The discrepancy in ovarian phenotypes between human patients and mutation-induced mice may reflect the inter-species differences in the expression pattern of NR5A1/Nr5a1 in immature ovaries. Nr5A1 transcripts are barely detectable in the murine ovary during the critical period for gonadal formation, whereas NR5A1 mRNA is continuously expressed in the human fetal ovary [4, 11]. It has been suggested that in the human fetal ovary, NR5A1 activates several anti-testis genes, such as CTNNB and WNT4 [5], and antagonizes nuclear receptor subfamily 0 group B member 1 (NR0B1) to suppress SOX9 expression [4, 6].…”

Section: Discussionmentioning

confidence: 99%

The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice

et al. 2016

Self Cite

View full text Add to dashboard Cite

NR5A1 is the key regulator of adrenal and gonadal development in both humans and mice. Recently, a missense substitution in human NR5A1, p.R92W, was shown to underlie gonadal dysgenesis in genetic males and testicular formation in genetic females. Here, we investigated the phenotypic effects of the p.R92W mutation on murine development. Mice carrying the p.R92W mutation manifested a similar but milder phenotype than that of the previously described Nr5a1 knockout mice. Importantly, mutation-positive XX mice showed no signs of masculinization. These results, together with prior observations, indicate that the p.R92W mutation in NR5A1/Nr5a1 encodes unique molecules that disrupt male gonadal development in both humans and mice and induces testicular formation specifically in human females. Our findings provide novel insights into the conservation and divergence in the molecular networks underlying mammalian sexual development.

show abstract

FOXL2 transcriptionally repressesSf1expression by antagonizing WT1 during ovarian development in mice

Cited by 45 publications

References 43 publications

Ex vivo cultures combined with vivo-morpholino induced gene knockdown provide a system to assess the role of WT1 and GATA4 during gonad differentiation

Ex vivo cultures combined with vivo-morpholino induced gene knockdown provide a system to assess the role of WT1 and GATA4 during gonad differentiation

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice

Contact Info

Product

Resources

About