Retinoblastoma protein represses E2F3 to maintain Sertoli cell quiescence in mouse testis

Rotgers, Emmi; Cisneros-Montalvo, Sheyla; Nurmio, Mirja; Toppari, Jorma

doi:10.1242/jcs.229849

Cited by 7 publications

(18 citation statements)

References 66 publications

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“…Prolonged AMH expression in the KO mice suggests that SCs are in a sustained 'immature' state of proliferation and therefore unable to fulfil nurse-like and scaffolding roles required for successful spermatogenesis. This suggestion is supported by the upregulation of further genes, such as the above-mentioned genes (Inha and Inhbb) as well as Thra, Krt18 (markers for immature SCs [113,122]), Fshr, Fgf9 and Kitl (also known as SCF).…”

Section: Discussionmentioning

confidence: 83%

“…Recent studies, however, supposed that SCs are rather in a state of continuous cell cycle repression and that the non-proliferative state of adult SCs is maintained by RB1 [129][130][131]. Rotgers and colleagues have shown that repression of the transcription factor E2F3 by RB1 is decisive for the maintenance of cell cycle quiescence in adult SCs [122]. Loss of Rb1 leads to impaired cell cycle control in the form of cell cycle re-entry mediated by E2F3 and hence to increased SC proliferation and loss of SC function [122,131].…”

Section: Discussionmentioning

confidence: 99%

“…Rotgers and colleagues have shown that repression of the transcription factor E2F3 by RB1 is decisive for the maintenance of cell cycle quiescence in adult SCs [122]. Loss of Rb1 leads to impaired cell cycle control in the form of cell cycle re-entry mediated by E2F3 and hence to increased SC proliferation and loss of SC function [122,131]. Furthermore, follistatin (Fst) expression was found to be increased in the absence of Rb1, which seems to be due to a potentially E2F3-mediated mechanism [122].…”

Section: Discussionmentioning

confidence: 99%

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Loss of Cx43 in Murine Sertoli Cells Leads to Altered Prepubertal Sertoli Cell Maturation and Impairment of the Mitosis-Meiosis Switch

Hilbold

Distl

Hoedemaker

et al. 2020

Cells

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Male factor infertility is a problem in today’s society but many underlying causes are still unknown. The generation of a conditional Sertoli cell (SC)-specific connexin 43 (Cx43) knockout mouse line (SCCx43KO) has provided a translational model. Expression of the gap junction protein Cx43 between adjacent SCs as well as between SCs and germ cells (GCs) is known to be essential for the initiation and maintenance of spermatogenesis in different species and men. Adult SCCx43KO males show altered spermatogenesis and are infertile. Thus, the present study aims to identify molecular mechanisms leading to testicular alterations in prepubertal SCCx43KO mice. Transcriptome analysis of 8-, 10- and 12-day-old mice was performed by next-generation sequencing (NGS). Additionally, candidate genes were examined by qRT-PCR and immunohistochemistry. NGS revealed many significantly differentially expressed genes in the SCCx43KO mice. For example, GC-specific genes were mostly downregulated and found to be involved in meiosis and spermatogonial differentiation (e.g., Dmrtb1, Sohlh1). In contrast, SC-specific genes implicated in SC maturation and proliferation were mostly upregulated (e.g., Amh, Fshr). In conclusion, Cx43 in SCs appears to be required for normal progression of the first wave of spermatogenesis, especially for the mitosis-meiosis switch, and also for the regulation of prepubertal SC maturation.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Loss of Cx43 in Murine Sertoli Cells Leads to Altered Prepubertal Sertoli Cell Maturation and Impairment of the Mitosis-Meiosis Switch

Hilbold

Distl

Hoedemaker

et al. 2020

Cells

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“…To quantify the number of Sertoli and Leydig cells, indirect immunofluorescence was performed as described previously 58 . Briefly, antigens were retrieved from sections of PFA fixed testes with 0.1 M citrate buffer, pH 6 at 95 °C, and autofluorescence blocked by incubation in 0.1 M NH 4 Cl.…”

Section: Methodsmentioning

confidence: 99%

Generation, localization and functions of macrophages during the development of testis

et al. 2020

Self Cite

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In the testis, interstitial macrophages are thought to be derived from the yolk sac during fetal development, and later replaced by bone marrow-derived macrophages. By contrast, the peritubular macrophages have been reported to emerge first in the postnatal testis and solely represent descendants of bone marrow-derived monocytes. Here, we define new monocyte and macrophage types in the fetal and postnatal testis using high-dimensional single-cell analyses. Our results show that interstitial macrophages have a dominant contribution from fetal liver-derived precursors, while peritubular macrophages are generated already at birth from embryonic precursors. We find that bone marrow-derived monocytes do not substantially contribute to the replenishment of the testicular macrophage pool even after systemic macrophage depletion. The presence of macrophages prenatally, but not postnatally, is necessary for normal spermatogenesis. Our multifaceted data thus challenge the current paradigms in testicular macrophage biology by delineating their differentiation, homeostasis and functions.

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“…Several transcription factors have been demonstrated to be essential for Sertoli cell proliferation. The major function of Rb1 is to suppress E2F transcription factors and knockout transcription factor E2F3 in Sertoli cells rescued the phenotype in Rb1 conditional knockout animals [ 25 ]. Transcription factors upstream stimulatory factor (USF) 1 and USF2 are expression in Sertoli cells and Usf1 knockout mice showed defects in spermatogenesis [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

E4 Transcription Factor 1 (E4F1) Regulates Sertoli Cell Proliferation and Fertility in Mice

Yan

Yang

2020

Animals

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In the mammalian testes, Sertoli cells are the only somatic cells in the seminiferous tubules that provide structural, nutritional and regulatory support for developing spermatogenic cells. Sertoli cells only proliferate during the fetal and neonatal periods and enter a quiescent state after puberty. Functional evidences suggest that the size of Sertoli cell population determines sperm production and fertility. However, factors that direct Sertoli cell proliferation and maturation are not fully understood. Transcription factor E4F1 is a multifunctional protein that serves essential roles in cell fate decisions and because it interacts with pRB, a master regulator of Sertoli cell function, we hypothesized that E4F1 may have a functional role in Sertoli cells. E4f1 mRNA was present in murine testis and immunohistochemical staining confirmed that E4F1 was enriched in mature Sertoli cells. We generated a conditional knockout mouse model using Amh-cre and E4f1flox/flox lines to study E4F1 fucntion in Sertoli cells and the results showed that E4f1 deletion caused a significant reduction in testis size and fertility. Further analyses revealed that meiosis progression and spermiogenesis were normal, however, Sertoli cell proliferation was impaired and germ cell apoptosis was elevated in the testis of E4f1 conditional knockout mice. On the basis of these findings, we concluded that E4F1 was expressed in murine Sertoli cells and served important functions in regulating Sertoli cell proliferation and fertility.

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Retinoblastoma protein represses E2F3 to maintain Sertoli cell quiescence in mouse testis

Cited by 7 publications

References 66 publications

Loss of Cx43 in Murine Sertoli Cells Leads to Altered Prepubertal Sertoli Cell Maturation and Impairment of the Mitosis-Meiosis Switch

Loss of Cx43 in Murine Sertoli Cells Leads to Altered Prepubertal Sertoli Cell Maturation and Impairment of the Mitosis-Meiosis Switch

Generation, localization and functions of macrophages during the development of testis

E4 Transcription Factor 1 (E4F1) Regulates Sertoli Cell Proliferation and Fertility in Mice

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