SOX4 regulates gonad morphogenesis and promotes male germ cell differentiation in mice

Zhao, Liang; Arsenault, Michel; Ng, Ee Ting; Longmuss, Enya; Chau, Tevin Chui-Ying; Hartwig, Sunny; Koopman, Peter

doi:10.1016/j.ydbio.2017.01.013

Cited by 43 publications

(30 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1A-D), However, the elongation of the gonads resolved by P0. Since a similar phenotype was reported in Sox4-/- mice [22], we examined the expression levels of Sox4 in the XX Tg-A gonads at 15.5 dpc and indeed found significantly reduced expression of Sox4 (Fig. S1E), suggesting that elevated NR5A1 repressed Sox4 resulting in abnormal morphology of the fetal ovaries.…”

Section: Resultssupporting

confidence: 69%

Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

Nomura

Kashimada

Suzuki

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

26The nuclear receptor NR5A1 (also known as Ad4BP, or SF1) is essential for the initial steps 27 of mammalian gonadal development. The Nr5a1 gene is equally expressed in XX and XY 28 gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in 29 XX gonads. We recently reported a case of 46, XX disorder of sex development (DSD) in 30 which ectopically expressed NR5A1 in XX gonads led to an ovo-testicular phenotype, 31 suggesting that excess NR5A1 can direct the development of immature XX gonads towards 32 testicular formation. However, a direct causal relationship has not been demonstrated in an 33 animal model. Here, using a Wt1-BAC (bacterial artificial chromosome) transgene system, 34 we generated two lines of mice overexpressing Nr5a1 in the fetal gonads at different levels.35 One of these lines (Tg-S), highly expressing Nr5a1, revealed that enforced Nr5a1 expression 36 alone is insufficient to switch the fate of the 46,XX gonads toward testicular formation in 37 mice. In the other line (Tg-A) expressing Nr5a1 at lower level, ovarian development was 38 compromised, with multi-oocyte follicles, reduced number of matured follicles, and impaired 39 expression of Wnt4, resulting in late onset infertility at 20 weeks after birth. The phenotype 40 was similar to that of genetically modified mice with impaired Notch signaling. Indeed, the 41 expression level of Notch2 and 3 was significantly reduced in Tg-A mice, and the ovarian 42 phenotype in Tg-A mice was almost completely rescued by in utero treatment with a Notch2 43 agonist HMN2-29. We conclude that suppression of Nr5a1 during the fetal period optimizes 44 ovarian development by fine tuning of Notch signaling levels. 45( 257 words) 46 47 AUTHOR SUMMARY 48 Sexual development is a process of differentiation from undifferentiated bipotential gonads, 3 50 understanding of organogenesis. The nuclear receptor NR5A1 which is essential for 51 mammalian gonadal development, is equally expressed in both gonadal primordia, but after 52 sex determination, is up-regulated in XY and down-regulated in XX gonads. We have 53 recently demonstrated that this down-regulation is mediated by ovarian transcription factor, 54 Forkhead box L2 (FOXL2). This finding raised two key questions, whether Nr5a1 can 55 function as a male sex-determining factor, and whether the repression is essential for 56 appropriate ovarian development. By generating two lines Tg mice in XX gonads with 57 different enforced expression levels of Nr5a1, our present study revealed that alterations in 58 Nr5a1 dosage, either reduced or excessive, result in pathological effects in ovarian 59 development and female fertility, indicating that the precise control of Nr5a1 at the 60 transcriptional level is essential for optimal ovarian development. We envisage that the 61 improved understanding of how this pathway regulates ovarian development and female 62 fertility would aid the development of artificial somatic ovarian cells, which in turn may 63 provide a valuable treatment option...

show abstract

Section: Resultssupporting

confidence: 69%

Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

Nomura

Kashimada

Suzuki

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, at postnatal day (P) 0, the shape of the ovaries in Tg-A mice was similar to that in wildtype mice, indicating that the elongation of the gonads had resolved by that stage. Since a similar phenotype was reported in Sox4 −/− mice (Zhao et al, 2017), we examined the expression levels of Sox4 in the XX Tg-A gonads at 15.5 dpc and indeed found significantly reduced expression of Sox4 (Fig. S3E).…”

Section: Overexpression Of Nr5a1 Fails To Cause XX Sex Reversal In Micesupporting

confidence: 71%

Nr5a1 suppression during the murine fetal period optimizes ovarian development by fine-tuning Notch signaling

Nomura

Kashimada

Suzuki

et al. 2019

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but, after sex determination, it is upregulated in XY testes and downregulated in XX ovaries. We have recently demonstrated, in mice, that this downregulation is mediated by forkhead box L2 (FOXL2) and hypothesized that adequate suppression of Nr5a1 is essential for normal ovarian development. Further, analysis of human patients with disorders/differences of sex development suggests that overexpression of NR5A1 can result in XX (ovo)testicular development. Here, we tested the role of Nr5a1 by overexpression in fetal gonads using a Wt1-BAC (bacterial artificial chromosome) transgene system. Enforced Nr5a1 expression compromised ovarian development in 46,XX mice, resulting in late-onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of Notch2 was significantly reduced in Nr5a1 transgenic mice, and the ovarian phenotype was almost completely rescued by in utero treatment with a NOTCH2 agonist. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by finetuning Notch signaling.

show abstract

“…However, we noticed the progenitor cells express genes involved in negative regulation of cell differentiation during the same time frame of Sertoli cell differentiation. Notably, we found Sox11 which has been recently identified as a potential 18, 2017; 13 co-repressor of the pro-Sertoli gene Sox9 (Zhao et al, 2017), as well as Sfrp1, a negative regulator of Wnt signaling pathway (Gauger et al, 2013). Possibly, the progenitor cells have a repression program allowing cells to escape the Sertoli cell fate and conserve a progenitor identity, similarly to a stem cell renewal process.…”

Section: Wt1mentioning

confidence: 71%

“…http://dx.doi.org/10.1101/190264 doi: bioRxiv preprint first posted online Sep. 18, 2017; Zhao, L., Arsenault, M., Ng, E.T., Longmuss, E., Chau, T.C.-Y., Hartwig, S., and Koopman, P. (2017). SOX4 regulates gonad morphogenesis and promotes male germ cell differentiation in mice.…”

mentioning

confidence: 99%

Deciphering cell lineage specification during male sex determination with single-cell RNA sequencing

Stévant

Neirijnck

Borel

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

SOX4 regulates gonad morphogenesis and promotes male germ cell differentiation in mice

Cited by 43 publications

References 79 publications

Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

Nr5a1 suppression during the murine fetal period optimizes ovarian development by fine-tuning Notch signaling

Deciphering cell lineage specification during male sex determination with single-cell RNA sequencing

Contact Info

Product

Resources

About