Oct4 is required for primordial germ cell survival

Kehler, James; Tolkunova, Elena; Koschorz, Birgit; Pesce, Maurizio; Gentile, Luca; Boiani, Michele; Lomelı́, Hilda; Nagy, András; McLaughlin, K. John; Schöler, Hans R.; Tomilin, Alexey

doi:10.1038/sj.embor.7400279

Cited by 514 publications

(417 citation statements)

References 23 publications

(48 reference statements)

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“…In this work, we investigated the role of Sox2 during mouse gametogenesis. Our results reveal that Sox2 deletion during the establishment of germ cell lineage impairs PGC development, as previously shown for Prdm14 [16], Oct4 [17,18], and Nanog [19]. We also found that Sox2 is essential for PGC proliferation in vivo and in vitro, and that it affects the expression of genes which are critical for their development.…”

Section: Introductionsupporting

confidence: 65%

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Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

et al. 2013

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Sox2 is a pluripotency-conferring gene expressed in primordial germ cells (PGCs) and postnatal oocytes, but the role it plays during germ cell development and early embryogenesis is unknown. Since Sox2 ablation causes early embryonic lethality shortly after blastocyst implantation, we generated mice bearing Sox2-conditional deletion in germ cells at different stages of their development through the Cre/loxP recombination system. Embryos lacking Sox2 in PGCs show a dramatic decrease of germ cell numbers at the time of their specification. At later stages, we found that Sox2 is strictly required for PGC proliferation. On the contrary, Sox2 deletion in meiotic oocytes does not impair postnatal oogenesis and early embryogenesis, indicating that it is not essential for oocyte maturation or for zygotic development. We also show that Sox2 regulates Kit expression in PGCs and binds to discrete transcriptional regulatory sequences of this gene, which is known to be important for PGCs survival and proliferation. Sox2 also stimulates the expression of Zfp148, which is required for normal development of fetal germ cells, and Rif1, a potential regulator of PGC pluripotency.

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Section: Introductionsupporting

confidence: 65%

“…These deleters, obtained by knocking Cre into the TNAP (tissue nonspecific alkaline phosphatase) locus, mediate Cre excision in PGCs between 9.0 and 10.5 dpc [17,30] (Fig. 1D).…”

Section: Sox2 Is Required For Pgc Development and Pluripotencymentioning

confidence: 99%

Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

et al. 2013

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“…14,16,26 The presence of this protein is essential for pluripotency of embryonic stem cells; and early in development, expression becomes confined to the germ cell lineage. Loss of OCT3/4 expression in mouse primordial germ cells leads to apoptosis, 27 and thus is required for their survival. Upon differentiation of primordial germ cells/gonocytes to either pre-spermatogonia or oogonia, OCT3/4 is lost.…”

Section: Discussionmentioning

confidence: 99%

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

et al. 2009

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Patients with disorders of sex development (DSD), especially those with gonadal dysgenesis and hypovirilization, are at risk of developing the so-called type II germ cell tumors (GCTs). Both carcinoma in situ and gonadoblastoma (GB) can be the precursor lesion, resulting in a seminomatous or nonseminomatous invasive cancer. SRY mutations residing in the HMG domain are found in 10 -15% of 46,XY gonadal dysgenesis cases. This domain contains two nuclear localization signals (NLSs). In this study, we report a unique case of a phenotypical normal woman, diagnosed as a patient with 46,XY gonadal dysgenesis, with an NLS missense mutation, on the basis of the histological diagnosis of a unilateral GB. The normal role of SRY in gonadal development is the upregulation of SOX9 expression. The premalignant lesion of the initially removed gonad was positive for OCT3/4, TSPY and stem cell factor in germ cells, and for FOXL2 in the stromal component (ie, granulosa cells), but not for SOX9. On the basis of these findings, prophylactical gonadectomy of the other gonad was performed, also showing a GB lesion positive for both FOXL2 (ovary) and SOX9 (testis). The identified W70L mutation in the SRY gene resulted in a 50% reduction in the nuclear accumulation of the mutant protein compared with wild type. This likely explains the diminished SOX9 expression, and therefore the lack of proper Sertoli cell differentiation during development. This case shows the value of the proper diagnosis of human GCTs in identification of patients with DSD, which allows subsequent early diagnosis and prevention of the development of an invasive cancer, likely to be treated by chemotherapy at young age.

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“…In the adult, Oct4 is exclusively expressed in germ cells, and had been detected in stem-cell populations such as bone marrow multipotent adult progenitors, haematopoietic stem cells, and stem cells that reside in epidermal basal layers 78,79 . More recent studies demonstrate that OCT4 is essential for germ-cell maintenance, but dispensable for somatic stem-cell self-renewal 80,81 . The importance of strictly maintaining Oct4 expression levels has been demonstrated both in vitro and in vivo: even a two-fold change in OCT4 protein abundance can cause ES cells to lose pluripotency 82 , and ectopic Oct4 expression promotes epithelial dysplasia in transgenic mice 83 .…”

Section: Oct4 Regulation By O 2 Levelsmentioning

confidence: 99%

The role of oxygen availability in embryonic development and stem cell function

Simon¹,

Keith²

2008

Nat Rev Mol Cell Biol

835

770

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Low levels of oxygen (O 2 ) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O 2 homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system, and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O 2 regulates their differentiation. Recent work has revealed an important link between factors involved in regulating stem/progenitor cell behaviour and hypoxiainducible factors, which provides a molecular framework for hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.

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Oct4 is required for primordial germ cell survival

Cited by 514 publications

References 23 publications

Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma

The role of oxygen availability in embryonic development and stem cell function

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