GATA4 regulates Sertoli cell function and fertility in adult male mice☆

Kyrönlahti, Antti; Euler, Rosemarie; Bielińska, Małgorzata; Schoeller, Erica L.; Moley, Kelle H.; Toppari, Jorma; Heikinheimo, Markku; Wilson, David B.

doi:10.1016/j.mce.2010.12.019

Cited by 102 publications

(89 citation statements)

References 77 publications

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“…Abnormal seminiferous tubular architecture accompanied with irregularly arranged germ cells, vacuoles, and giant cells in the gonadspecific Nr5a1 KO testes became apparent by P14. Intratubular vacuoles have been reported in other KO mice, in which spermatogenesis was impaired and is associated with Sertoli cell damage (Hellsten et al 2002, Kyrönlahti et al 2011. In fact, we observed that many of the vacuoles detected in the KO mice were accompanied by a nucleus positive for the Sertoli cell marker SOX9 (Fig.…”

Section: (A B C D E F G and H) Representative Images Of Immunoesupporting

confidence: 67%

NR5A1 is required for functional maturation of Sertoli cells during postnatal development

Kato

Esaki²,

Matsuzawa³

et al. 2012

Reproduction

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The orphan nuclear receptor steroidogenic factor 1 (NR5A1 (SF-1)) is expressed in both Sertoli and Leydig cells in the testes. This study investigates the postnatal development of the testes of a gonad-specific Nr5a1 knockout (KO) mouse, in which Nr5a1 was specifically inactivated. The KO testes appeared histologically normal from postnatal day 0 (P0) until P7. However, disorganized germ cells, vacuoles, and giant cells appeared by P14 in the seminiferous tubules of KO but not control mice. Expression of NR5A1 and various factors was examined by immunohistochemistry (IHC). The number of NR5A1-positive Sertoli cells in the KO testes was lower compared with controls at all the developmental stages and decreased to nearly undetectable levels by P21. IHC for anti-Mü llerian hormone and p27, immature and mature Sertoli cell markers, respectively, indicated a delay in Sertoli cell maturation in the KO testes. The number of Sertoli cell-expressing factors involved in Sertoli cell differentiation including WT1, SOX9, GATA4, and androgen receptor were lower in the KO testes compared with controls. Furthermore, fewer proliferating cell nuclear antigen-positive proliferative germ cells were observed, and the number of TUNEL-labeled cells was significantly higher in the KO testes compared with controls at P14 and P21, indicating impaired spermatogenesis. IHC for CYP11A1 (SCC) indicated the presence of steroidogenic Leydig cells in the interstitium of the KO testes at all stages examined. These results suggest that NR5A1 is essential for Sertoli cell maturation and therefore spermatogenesis, during postnatal testis development.

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Section: (A B C D E F G and H) Representative Images Of Immunoesupporting

confidence: 67%

NR5A1 is required for functional maturation of Sertoli cells during postnatal development

Kato

Esaki²,

Matsuzawa³

et al. 2012

Reproduction

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“…Similar defects also occur in mouse testes lacking the fibronectin domain-containing protein FNDC3A (originally described as the symplastic spermatid "sys" mutation [37,54]), the glycosylated cell adhesion molecule Cadm1 (55,56), the multifunctional glycoprotein Basigin (57), and the glycosyltransferase Mgat1 (58). Strikingly, loss of Sertoli cell-restricted proteins (Cib1, Inpp5b, and Gata4) also results in apoptosis of germ cells and MNC formation (59)(60)(61), further highlighting the importance of germ-Sertoli cell interaction. Notably, cKO MNCs displayed apoptotic features, including chromatin condensation and cell shrinkage, but were TUNEL negative, suggesting that apoptosis of spermatocytes and spermatids in cKO testes may occur via distinct mechanisms.…”

Section: Discussionmentioning

confidence: 81%

RNA Binding Protein Ptbp2 Is Essential for Male Germ Cell Development

Zagore

Grabinski

Sweet

et al. 2015

Molecular and Cellular Biology

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dRNA binding proteins (RBPs) are increasingly recognized as essential factors in tissue development and homeostasis. The polypyrimidine tract binding (PTB) protein family of RBPs are important posttranscriptional regulators of gene expression. In the nervous system, the function and importance of PTB protein 2 (Ptbp2) as a key alternative splicing regulator is well established. Ptbp2 is also abundantly expressed during spermatogenesis, but its role in this developmental program has not been explored. Additionally, the importance of alternative splicing regulation in spermatogenesis is unclear. Here, we demonstrate that Ptbp2 is essential for spermatogenesis. We also describe an improved dual fluorescence flow cytometry strategy to discriminate, quantify, and collect germ cells in different stages of development. Using this approach, in combination with traditional histological methods, we show that Ptbp2 ablation results in germ cell loss due to increased apoptosis of meiotic spermatocytes and postmeiotic arrest of spermatid differentiation. Furthermore, we show that Ptbp2 is required for alternative splicing regulation in the testis, as in brain. Strikingly, not all of the alternatively spliced RNAs examined were sensitive to Ptbp2 loss in both tissues. Collectively, the data provide evidence for an important role for alternative splicing regulation in germ cell development and a central role for Ptbp2 in this process.T issue-restricted RNA binding proteins (RBPs) have central roles in posttranscriptional regulatory events necessary for tissue development and the specialization of cell functions. Through interactions with nascent transcripts, RBPs can impact alternative splicing and polyadenylation, two highly regulated processes that permit genes to generate multiple RNA isoforms with different combinations of coding and noncoding sequences. Further proteome diversity and control are imparted by RBPs that act on mature mRNAs to alter stability and translation. Accordingly, changes in the levels/activity of specific RBPs underlie key transcriptome and proteome remodeling events that drive multiple developmental pathways (1, 2).The polypyrimidine tract binding (PTB) proteins are among a group of multifunctional RBPs that have key roles in tissue-specific posttranscriptional programs (3-5). While Ptbp1 is expressed in most tissues, Ptbp2 (also called brain or neuronal PTB protein [br/nPTB]) is more tissue restricted, with high levels of expression in brain and testis (6-8). Despite their high sequence similarity, Ptbp1 and Ptbp2 regulate the alternative splicing (AS) of overlapping but nonredundant sets of mRNA targets, with some AS exons more strongly repressed by one PTB protein paralog than the other (9-12). Accordingly, a switch in PTB protein expression from Ptbp1 to Ptbp2 is associated with changes in the expression of AS isoforms during neuronal differentiation (9, 10). Ptbp2 is an essential AS factor in the developing nervous system, where it has a prominent role in repressing AS exons that are enriched i...

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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%

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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GATA4 regulates Sertoli cell function and fertility in adult male mice☆

Cited by 102 publications

References 77 publications

NR5A1 is required for functional maturation of Sertoli cells during postnatal development

NR5A1 is required for functional maturation of Sertoli cells during postnatal development

RNA Binding Protein Ptbp2 Is Essential for Male Germ Cell Development

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

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