Transgenic mouse models in the study of reproduction: insights into GATA protein function

Tevosian, Sergei G.

doi:10.1530/rep-14-0086

Cited by 28 publications

(31 citation statements)

References 108 publications

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“…Consistent with this expression pattern, different genetic mouse models have begun to illuminate the complex and essential roles played by this transcription factor in the very first steps of gonadal development and later, for male and female fertility (Kyrönlahti et al 2011a,b, Manuylov et al 2011, Bennett et al 2012, Efimenko et al 2013, Hu et al 2013, Tevosian 2014. While these studies clearly established the essential nature of GATA4 in reproduction, understanding how GATA4 accomplishes these tasks, i.e., identifying its target genes and thus its mechanism of action, remains incomplete.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with its very early expression at the stage of coelomic epithelial thickening, conditionally Gata4-deficient XX or XY embryos do not initiate the formation of a genital ridge (Hu et al 2013). Elegant mouse models used by Tevosian et al, where the Gata4 gene was excised around the time of sex determination by gonadspecific Cre drivers, have shown that GATA4 is also essential for normal testicular and ovarian differentiation (reviewed in Tevosian (2014)). These crucial functions in early mammalian gonadogenesis necessitate not only GATA4 but also a functional cooperation between GATA4 and its transcriptional partner Friend of GATA 2 (FOG2/ZFPM2; Tevosian et al 2002, Manuylov et al 2008.…”

Section: Introductionmentioning

confidence: 93%

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GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

Bergeron¹,

Nadeau²,

Viger³

2015

Reproduction

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GATA4 is an essential transcription factor required for the initiation of genital ridge formation, for normal testicular and ovarian differentiation at the time of sex determination, and for male and female fertility in adulthood. In spite of its crucial roles, the genes and/or gene networks that are ultimately regulated by GATA4 in gonadal tissues remain to be fully understood. This is particularly true for the steroidogenic lineages such as Leydig cells of the testis where many in vitro (promoter) studies have provided good circumstantial evidence that GATA4 is a key regulator of Leydig cell gene expression and steroidogenesis, but formal proof is still lacking. We therefore performed a microarray screening analysis of MA-10 Leydig cells in which Gata4 expression was knocked down using an siRNA strategy. Analysis identified several GATA4-regulated pathways including cholesterol synthesis, cholesterol transport, and especially steroidogenesis. A decrease in GATA4 protein was associated with decreased expression of steroidogenic genes previously suspected to be GATA4 targets such as Cyp11a1 and Star. Gata4 knockdown also led to an important decrease in other novel steroidogenic targets including Srd5a1, Gsta3, Hsd3b1, and Hsd3b6, as well as genes known to participate in cholesterol metabolism such as Scarb1, Ldlr, Soat1, Scap, and Cyp51. Consistent with the decreased expression of these genes, a reduction in GATA4 protein compromised the ability of MA-10 cells to produce steroids both basally and under hormone stimulation. These data therefore provide strong evidence that GATA4 is an essential transcription factor that sits atop of the Leydig cell steroidogenic program.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

Bergeron¹,

Nadeau²,

Viger³

2015

Reproduction

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“…Ovarian development is promoted by complementation of the transcription factor FOXL2 (forkhead box L2) and RSPO1 (R-spondin homolog 1)/WNT4 (winglessrelated MMTV integration site 4)/β-catenin signalling in GATA4-expressing supporting cells , Tevosian 2014. During early ovarian development, proliferative GATA4-expressing cells activate expression of the cell cycle inhibitor p27KIP1 (p27) and FOXL2 as they form non-proliferative granulosa cells (Mork et al 2012, Rastetter et al 2014, Gustin et al 2016.…”

Section: Introductionmentioning

confidence: 99%

FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

et al. 2016

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Testis development is dependent on the key sex-determining factors SRY and SOX9, which activate the essential ligand FGF9. Although FGF9 plays a central role in testis development, it is unable to induce testis formation on its own. However, other growth factors, including activins and TGFβs, also present testis during testis formation. In this study, we investigated the potential of FGF9 combined with activin and TGFβ to induce testis development in cultured XX gonads. Our data demonstrated differing individual and combined abilities of FGF9, activin and TGFβ to promote supporting cell proliferation, Sertoli cell development and male germ line differentiation in cultured XX gonads. FGF9 promoted proliferation of supporting cells in XX foetal gonads at rates similar to those observed in vivo during testis cord formation in XY gonads but was insufficient to initiate testis development. However, when FGF9, activin and TGFβ were combined, aspects of testicular development were induced, including the expression of Sox9, morphological reorganisation of the gonad and deposition of laminin around germ cells. Enhancing β-catenin activity diminished the testis-promoting activities of the combined growth factors. The male promoting activity of FGF9 and the combined growth factors directly or indirectly extended to the germ line, in which a mixed phenotype was observed. FGF9 and the combined growth factors promoted male germ line development, including mitotic arrest, but expression of pluripotency genes was maintained, rather than being repressed. Together, our data provide evidence that combined signalling by FGF9, activin and TGFβ can induce testicular characteristics in XX gonads.Reproduction (2016) 152 529-543

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“…In the testis, GATA-4 regulates SC differentiation and function and is required for proper interaction between these somatic cells and germ cells. 45,49,50 In the conditional knockout of GATA-4, the testis was atrophic, with impairment of spermatogenesis and loss of fertility. Most importantly, SCs exhibited altered morphology and had increased permeability at the blood-testis barrier, 45 consistent with an immature phenotype.…”

Section: 1338-40mentioning

confidence: 99%

Sertoli cells are capable of proliferation into adulthood in the transition region between the seminiferous tubules and therete testisin Wistar rats

et al. 2016

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Sertoli cells (SCs) play a crucial role in testis differentiation, development and function, determining the magnitude of sperm production in sexually mature animals. For over 40 years, it has been considered that these key testis somatic cells stop dividing during early pre-pubertal phase, between around 10 to 20 days after birth respectively in mice and rats, being after that under physiological conditions a stable and terminally differentiated population. However, evidences from the literature are challenging this dogma. In the present study, using several important functional markers (Ki-67, BrdU, p27, GATA-4, Androgen Receptor), we investigated the SC differentiation status in 36 days old and adult Wistar rats, focusing mainly in the transition region (TR) between the seminiferous tubules (ST) and the rete testis. Our results showed that SCs in TR remain undifferentiated for a longer period and, although at a lesser degree, even in adult rats proliferating SCs were observed in this region. Therefore, these findings suggest that, different from the other ST regions investigated, SCs residing in the TR exhibit a distinct functional phenotype. These undifferentiated SCs may compose a subpopulation of SC progenitors that reside in a specific microenvironment capable of growing the ST length if needed from this particular testis region. Moreover, our findings demonstrate an important aspect of testis function in mammals and opens new venues for other experimental approaches to the investigation of SC physiology, spermatogenesis progression and testis growth. Besides that, the TR may represent an important site for pathophysiological investigations and cellular interactions in the testis.

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Transgenic mouse models in the study of reproduction: insights into GATA protein function

Cited by 28 publications

References 108 publications

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway

FGF9, activin and TGFβ promote testicular characteristics in an XX gonad organ culture model

Sertoli cells are capable of proliferation into adulthood in the transition region between the seminiferous tubules and therete testisin Wistar rats

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