Talk:Primordial Germ Cell Development

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2014

Generation of mouse functional oocytes in rat by xeno-ectopic transplantation of primordial germ cells

Biol Reprod. 2014 Oct;91(4):89. doi: 10.1095/biolreprod.114.121640. Epub 2014 Aug 27.

Hayama T1, Yamaguchi T2, Kato-Itoh M1, Hamanaka S1, Kawarai M1, Sanbo M3, Tamura C3, Lee YS1, Yanagida A1, Murayama H1, Mizuno N1, Umino A1, Sato H1, Yamazaki S1, Masaki H1, Kobayashi T1, Hirabayashi M3, Nakauchi H4.

Abstract

Primordial germ cells (PGCs) are germ cell progenitors in the fetal genital ridge; female PGCs give rise to definitive oocytes that contribute to the next generation. Artificial PGCs have been induced in vitro from pluripotent stem cells and gonad-like tissue has been induced in vivo by cotransplantation of PGCs with PGC-free gonadal cells. To apply these technologies to human infertility treatment or conservation of rare species, PGC transplantation must be established in xenogenic animals. Here, we established a xenogeneic transplantation model by inducing ovary-like tissue from PGCs in xenogenic animals. We transplanted enzymatically dispersed PGCs with PGC-free gonadal cells under the kidney capsule of xenogenic immunodeficient animals. The transplanted cells formed ovary-like tissues under the kidney capsule. These tissues were histologically similar to the normal gonad and expressed the oocyte markers Vasa and Stella. In addition, mouse germinal vesicle-stage oocyte-like cells collected from ovary-like tissue in rats matured to metaphase II via in vitro maturation and gave rise to offspring by intracytoplasmic sperm injection. Our studies show that rat/mouse female PGCs and PGC-free gonadal cells can develop and reconstruct ovary-like tissue containing functional oocytes in an ectopic xenogenic microenvironment. © 2014 by the Society for the Study of Reproduction, Inc. KEYWORDS: PGC; oocyte; ovary-like tissue; xeno-ectopic transplantation

PMID 25165118

Sall4 is Essential for Mouse Primordial Germ Cell Specification by Suppressing Somatic Cell Program Genes

Stem Cells. 2014 Sep 29. doi: 10.1002/stem.1853. [Epub ahead of print]

Yamaguchi YL1, Tanaka SS, Kumagai M, Fujimoto Y, Terabayashi T, Matsui Y, Nishinakamura R.

Abstract

The Sall4 zinc finger protein is a critical transcription factor for pluripotency in embryonic stem cells (ESCs). It is also involved in the formation of a variety of organs, in mice and humans. We report the essential roles of Sall4 in mouse primordial germ cell (PGC) specification. PGC specification is accompanied by the activation of the stem cell program and repression of the somatic cell program in progenitor cells. Conditional inactivation of Sall4 during PGC specification led to a reduction in the number of PGCs in embryonic gonads. Sall4del/del PGCs failed to translocate from the mesoderm to the endoderm and underwent apoptosis. In Sall4del/del PGC progenitors, somatic cell program genes (Hoxa1 and Hoxb1) were de-repressed, while activation of the stem cell program was not impaired. We demonstrated that in differentiated ESCs, Sall4 bound to these somatic cell program gene loci, which are reportedly occupied by Prdm1 in embryonic carcinoma cells. Given that Sall4 and Prdm1 are known to associate with the histone deacetylase repressor complex, our findings suggest that Sall4 suppresses the somatic cell program possibly by recruiting the repressor complex in conjunction with Prdm1; therefore, it is essential for PGC specification. Stem Cells 2014. Copyright © 2014 AlphaMed Press. KEYWORDS: HDAC; Ifitm1; mouse; primordial germ cells (PGCs); spalt-like 4 (Sall4) PMID 25263278

Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis

Reprod Med Biol. 2014;13(4):203-215. Epub 2014 Jun 10.

Irie N, Tang WW, Azim Surani M.

Abstract Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms. How germ cells acquire this ability has been of considerable interest. In mammals, primordial germ cells (PGCs), the precursors of sperm and oocytes, are specified around the time of gastrulation. PGCs are induced by signals from the surrounding extra-embryonic tissues to the equipotent epiblast cells that give rise to all cell types. Currently, the mechanism of PGC specification in mammals is best understood from studies in mice. Following implantation, the epiblast cells develop as an egg cylinder while the extra-embryonic ectoderm cells which are the source of important signals for PGC specification are located over the egg cylinder. However, in most cases, including humans, the epiblast cells develop as a planar disc, which alters the organization and the source of the signaling for cell fates. This, in turn, might have an effect on the precise mechanism of PGC specification in vivo as well as in vitro using pluripotent embryonic stem cells. Here, we discuss how the key early embryonic differences between rodents and other mammals may affect the establishment of the pluripotency network in vivo and in vitro, and consequently the basis for PGC specification, particularly from pluripotent embryonic stem cells in vitro. KEYWORDS: Epiblast; Human; Mouse; Pluripotent stem cells; Primordial germ cells PMID 25298745

2011

Licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells

Proc Natl Acad Sci U S A. 2011 Apr 19. [Epub ahead of print]

Gill ME, Hu YC, Lin Y, Page DC. Source Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142.

Abstract Mammalian oocytes and spermatozoa derive from fetal cells shared by the sexes. These primordial germ cells (PGCs) migrate to the developing somatic gonad, giving rise to oocytes or spermatozoa. These opposing sexual fates are determined not by the PGCs' own sex chromosome constitution (XX or XY), but by the sexual identity of the fetal gonad that they enter. We asked whether PGCs undergo a developmental transition that enables them to respond to feminizing or masculinizing cues from fetal ovary or testis. We conducted in vivo genetic studies of DAZL, an RNA-binding protein expressed in both ovarian and testicular germ cells. We found that germ cells in C57BL/6 Dazl-deficient fetuses-whether XX or XY-migrate to the gonad but do not develop either male or female features. Instead, they remain in a sexually undifferentiated state similar to that of migrating PGCs. Thus, germ cells in C57BL/6 Dazl-deficient fetuses do not respond to sexual cues from ovary or testis, whereas the earlier processes of germ cell specification and migration are unaffected. We propose that PGCs of both XX and XY fetuses undergo licensing, an active developmental transition that enables the resultant gametogenesis-competent cells to respond to feminizing or masculinizing cues produced by the fetal ovary or testis and hence to embark on oogenesis or spermatogenesis. In C57BL/6 mice, Dazl is required for licensing. Licensing serves as a gateway from the embryonic processes shared between the sexes-germ cell specification and migration-to the sex-specific pathways of oogenesis and spermatogenesis.

PMID: 21504946 http://www.ncbi.nlm.nih.gov/pubmed/21504946

2009

Dazl functions in maintenance of pluripotency and genetic and epigenetic programs of differentiation in mouse primordial germ cells in vivo and in vitro

Haston KM, Tung JY, Reijo Pera RA. PLoS One. 2009 May 21;4(5):e5654.

BACKGROUND: Mammalian germ cells progress through a unique developmental program that encompasses proliferation and migration of the nascent primordial germ cell (PGC) population, reprogramming of nuclear DNA to reset imprinted gene expression, and differentiation of mature gametes. Little is known of the genes that regulate quantitative and qualitative aspects of early mammalian germ cell development both in vivo, and during differentiation of germ cells from mouse embryonic stem cells (mESCs) in vitro.

METHODOLOGY AND PRINCIPAL FINDINGS: We used a transgenic mouse system that enabled isolation of small numbers of Oct4DeltaPE:GFP-positive germ cells in vivo, and following differentiation from mESCs in vitro, to uncover quantitate and qualitative phenotypes associated with the disruption of a single translational regulator, Dazl. We demonstrate that disruption of Dazl results in a post-migratory, pre-meiotic reduction in PGC number accompanied by aberrant expression of pluripotency genes and failure to erase and re-establish genomic imprints in isolated male and female PGCs, as well as subsequent defect in progression through meiosis. Moreover, the phenotypes observed in vivo were mirrored by those in vitro, with inability of isolated mutant PGCs to establish pluripotent EG (embryonic germ) cell lines and few residual Oct-4-expressing cells remaining after somatic differentiation of mESCs carrying a Dazl null mutation. Finally, we observed that even within undifferentiated mESCs, a nascent germ cell subpopulation exists that was effectively eliminated with ablation of Dazl.

CONCLUSIONS AND SIGNIFICANCE: This report establishes the translational regulator Dazl as a component of pluripotency, genetic, and epigenetic programs at multiple time points of germ cell development in vivo and in vitro, and validates use of the ESC system to model and explore germ cell biology.

PMID: 19468308

Steel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration

Development. 2009 Apr;136(8):1295-303. Epub 2009 Mar 11.

Gu Y, Runyan C, Shoemaker A, Surani A, Wylie C.

Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Abstract Steel factor is an essential survival and proliferation factor for primordial germ cells (PGCs) during their migration in the early mouse embryo. PGCs arise during gastrulation, and migrate into the posterior endoderm that becomes the hindgut. Previous reports have suggested that PGCs become dependent on Steel factor when they colonize the hindgut. However, in the absence of a good marker for living PGCs, their behavior before hindgut colonization has not been previously studied. We report here the normal behavior of PGCs in live embryos before hindgut colonization, and the roles of Steel factor, using a reporter line in which GFP is driven by the promoter of the Stella gene, whose activation accompanies the initial specification of PGCs. We show first that PGCs are surrounded by Steel factor-expressing cells from their first appearance in the allantois to the time they enter the genital ridges. Second, fewer PGCs are found in the allantois in Steel-null embryos, but this is not due to a failure of PGC specification. Third, the analysis of cultured Steel-null early embryos shows that Steel factor is required for normal PGC motility, both in the allantois and in the hindgut. Germ cells migrate actively in the allantois, and move directionally from the allantois into the proximal epiblast. In the absence of Steel factor, caused by either null mutation or antibody blockade, PGC motility is dramatically decreased, but directionality is maintained, demonstrating a primary role for Steel factor in PGC motility. This was found both before and after colonization of the hindgut. These data, together with previously published data, show that PGCs are Steel factor dependent from their initial specification until they colonize the genital ridges, and suggest the existence of a ;spatio-temporal niche' that travels with this important pluripotential cell population in the embryo.

PMID: 19279135

2008

Analysis of chicken primordial germ cells

Motono M, Ohashi T, Nishijima K, Iijima S. Cytotechnology. 2008 Jun;57(2):199-205. Epub 2008 Jul 23. PMID: 19003166

Primordial germ cell specification from embryonic stem cells

Wei W, Qing T, Ye X, Liu H, Zhang D, Yang W, Deng H. PLoS One. 2008;3(12):e4013. Epub 2008 Dec 24.

BACKGROUND: Primordial germ cell (PGC) specification is the first crucial step in germ line development. However, owing to significant challenges regarding the in vivo system, such as the complex cellular environment and potential problems with embryo manipulation, it is desirable to generate embryonic stem (ES) cells that are capable of overcoming these aforementioned limitations in order to provide a potential in vitro model to recapitulate the developmental processes in vivo.

METHODOLOGY AND PRINCIPAL FINDINGS: Here, we studied the detailed process of PGC specification from stella-GFP ES cells. We first observed the heterogeneous expression of stella in ES cells. However, neither Stella-positive ES cells nor Stella-negative ES cells shared a similar gene expression pattern with either PGCs or PGC precursors. Second, we derived PGCs from ES cells using two differentiation methods, namely the attachment culture technique and the embryoid body (EB) method. Compared with PGCs derived via the attachment culture technique, PGCs derived via the EB method that had undergone the sequential erasure of Peg3 followed by Igf2r resulted in a cell line in which the expression dynamics of T, Fgf8 and Sox17, in addition to the expression of the epiblast markers, were more similar to the in vivo expression, thus demonstrating that the process of PGC derivation was more faithfully recapitulated using the EB method. Furthermore, we developed an in vitro model of PGC specification in a completely chemically defined medium (CDM) that indicated that BMP4 and Wnt3a promoted PGC derivation, whereas BMP8b and activinA had no observable effect on PGC derivation.

CONCLUSIONS AND SIGNIFICANCE: The in vitro model we have established can recapitulate the developmental processes in vivo and provides new insights into the mechanism of PGC specification.

PMID: 19107197

Figure 6 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602984/figure/pone-0004013-g006/

A potential model of PGC specification. Some of the cells in the ICM (inner cell mass)/ES cells were Stella and/or Blimp1 positive cells. with the development of the embryo, the expression of Blimp1 was depressed in these cells with the help of signals from neighboring cells. Later, induced by WNT and/or BMP signaling, a subpopulation of these cells with the expression of mesoderm markers emerged, some of which acquired the expression of Blimp1. Then, Blimp1 functions to repress the expression of somatic markers that were normally down-regulated in PGCs [34]. Subsequently, cells with the expression of both Blimp1 and Stella were fated to germ-line development.

2003

The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice

BMC Dev Biol. 2003 Mar 19;3:1. Epub 2003 Mar 19. Lange UC, Saitou M, Western PS, Barton SC, Surani MA.

Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK. ucl20@cam.ac.uk Abstract BACKGROUND: Specification of primordial germ cells in mice depends on instructive signalling events, which act first to confer germ cell competence on epiblast cells, and second, to impose a germ cell fate upon competent precursors. fragilis, an interferon-inducible gene coding for a transmembrane protein, is the first gene to be implicated in the acquisition of germ cell competence.

RESULTS: Here, we describe four additional fragilis-related genes, fragilis2-5, which are clustered within a 68 kb region in the vicinity of the fragilis locus on Chr 7. These genes exist in a number of mammalian species, which in the human are also clustered on the syntenic region on Chr 11. In the mouse, fragilis2 and fragilis3, which are proximate to fragilis, exhibit expression that overlaps with the latter in the region of specification of primordial germ cells. Using single cell analysis, we confirm that all these three fragilis-related genes are predominant in nascent primordial germ cells, as well as in gonadal germ cells.

CONCLUSION: The Fragilis family of interferon-inducible genes is tightly associated with germ cell specification in mice. Furthermore, its evolutionary conservation suggests that it probably plays a critical role in all mammals. Detailed analysis of these genes may also elucidate the role of interferons as signalling molecules during development.

PMID: 12659663