scholarly journals GATA transcription factors, SOX17 and TFAP2C, drive the human germ-cell specification program

2021 ◽  
Vol 4 (5) ◽  
pp. e202000974
Author(s):  
Yoji Kojima ◽  
Chika Yamashiro ◽  
Yusuke Murase ◽  
Yukihiro Yabuta ◽  
Ikuhiro Okamoto ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Cell ◽  
Cell Fate ◽  
Germ Line ◽  
Primordial Germ Cell ◽  
Bmp Signaling ◽  
Germ Cell Specification ◽  
Bona Fide ◽  
Underlying Mechanisms

The in vitro reconstitution of human germ-cell development provides a robust framework for clarifying key underlying mechanisms. Here, we explored transcription factors (TFs) that engender the germ-cell fate in their pluripotent precursors. Unexpectedly, SOX17, TFAP2C, and BLIMP1, which act under the BMP signaling and are indispensable for human primordial germ-cell-like cell (hPGCLC) specification, failed to induce hPGCLCs. In contrast, GATA3 or GATA2, immediate BMP effectors, combined with SOX17 and TFAP2C, generated hPGCLCs. GATA3/GATA2 knockouts dose-dependently impaired BMP-induced hPGCLC specification, whereas GATA3/GATA2 expression remained unaffected in SOX17, TFAP2C, or BLIMP1 knockouts. In cynomolgus monkeys, a key model for human development, GATA3, SOX17, and TFAP2C were co-expressed exclusively in early PGCs. Crucially, the TF-induced hPGCLCs acquired a hallmark of bona fide hPGCs to undergo epigenetic reprogramming and mature into oogonia/gonocytes in xenogeneic reconstituted ovaries. By uncovering a TF circuitry driving the germ line program, our study provides a paradigm for TF-based human gametogenesis.

scholarly journals Resf1 supports embryonic stem cell self-renewal and effective germline entry

2021 ◽  
Author(s):  
Matus Vojtek ◽  
Ian Chambers
Keyword(s):  
Stem Cells ◽  
Germ Cell ◽  
Germ Line ◽  
Primordial Germ Cell ◽  
Embryonic Stem ◽  
Cell Specification ◽  
Self Renewal ◽  
Downstream Target ◽  
Germ Cell Specification

Retroelement silencing factor 1 (Resf1) interacts with the key regulators of mouse embryonic stem cells (ESCs) Oct4 and Nanog, and its absence results in sterility of mice. However, the function of Resf1 in ESCs and germ line specification is poorly understood. In this study, we used Resf1 knockout cell lines to determine the requirements of RESF1 for ESCs self-renewal and for in vitro specification of ESCs into primordial germ cell-like cells (PGCLCs). We found that deletion of Resf1 in ESCs cultured in serum and LIF reduces self-renewal potential whereas episomal expression of RESF1 has a modest positive effect on ESC self-renewal. In addition, RESF1 is not required for the capacity of NANOG and its downstream target ESRRB to drive self-renewal in the absence of LIF. However, Resf1 deletion reduces efficiency of PGCLC differentiation in vitro. These results identify Resf1 as a novel player in the regulation of pluripotent stem cells and germ cell specification.

scholarly journals Quantitative analysis of signaling responses during mouse primordial germ cell specification

Biology Open ◽  
2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Sophie M. Morgani ◽  
Anna-Katerina Hadjantonakis
Keyword(s):  
Cell Fate ◽  
Primordial Germ Cells ◽  
Primordial Germ Cell ◽  
Small Population ◽  
Bmp Signaling ◽  
Pluripotent Cells ◽  
Cell Fate Decisions ◽  
Germ Cell Specification

ABSTRACT During early mammalian development, the pluripotent cells of the embryo are exposed to a combination of signals that drive exit from pluripotency and germ layer differentiation. At the same time, a small population of pluripotent cells give rise to the primordial germ cells (PGCs), the precursors of the sperm and egg, which pass on heritable genetic information to the next generation. Despite the importance of PGCs, it remains unclear how they are first segregated from the soma, and if this involves distinct responses to their signaling environment. To investigate this question, we mapped BMP, MAPK and WNT signaling responses over time in PGCs and their surrounding niche in vitro and in vivo at single-cell resolution. We showed that, in the mouse embryo, early PGCs exhibit lower BMP and MAPK responses compared to neighboring extraembryonic mesoderm cells, suggesting the emergence of distinct signaling regulatory mechanisms in the germline versus soma. In contrast, PGCs and somatic cells responded comparably to WNT, indicating that this signal alone is not sufficient to promote somatic differentiation. Finally, we investigated the requirement of a BMP response for these cell fate decisions. We found that cell lines with a mutation in the BMP receptor (Bmpr1a−/−), which exhibit an impaired BMP signaling response, can efficiently generate PGC-like cells revealing that canonical BMP signaling is not cell autonomously required to direct PGC-like differentiation.

scholarly journals Quantitative analysis of signaling responses during mouse primordial germ cell specification

2021 ◽  
Author(s):  
Sophie M. Morgani ◽  
Anna-Katerina Hadjantonakis
Keyword(s):  
Cell Fate ◽  
Primordial Germ Cells ◽  
Primordial Germ Cell ◽  
Small Population ◽  
Bmp Signaling ◽  
Pluripotent Cells ◽  
Cell Fate Decisions ◽  
Germ Cell Specification

AbstractDuring early mammalian development, the pluripotent cells of the embryo are exposed to a combination of signals that drive exit from pluripotency and germ layer differentiation. At the same time, a small population of pluripotent cells give rise to the primordial germ cells (PGCs), the precursors of the sperm and egg, which pass on heritable genetic information to the next generation. Despite the importance of PGCs, it remains unclear how they are first segregated from the soma, and if this involves distinct responses to their signaling environment. To investigate this question, we mapped BMP, MAPK and WNT signaling responses over time in PGCs and their surrounding niche in vitro and in vivo at single-cell resolution. We showed that, in the mouse embryo, early PGCs exhibit lower BMP and MAPK responses compared to neighboring extraembryonic mesoderm cells, suggesting the emergence of distinct signaling regulatory mechanisms in the germline versus soma. In contrast, PGCs and somatic cells responded comparably to WNT, indicating that this signal alone is not sufficient to promote somatic differentiation. Finally, we investigated the requirement of a BMP response for these cell fate decisions. We found that cell lines with a mutation in the BMP receptor (Bmpr1a−/−), which exhibit an impaired BMP signaling response, can efficiently generate PGC-like cells revealing that canonical BMP signaling is not cell autonomously required to direct PGC-like differentiation.

scholarly journals Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mikael G. Pezet ◽  
Aurora Gomez-Duran ◽  
Florian Klimm ◽  
Juvid Aryaman ◽  
Stephen Burr ◽  
...  
Keyword(s):  
Germ Cell ◽  
Oxygen Tension ◽  
Germ Line ◽  
Embryonic Stem ◽  
Mitochondrial Diseases ◽  
Genetic Bottleneck ◽  
Cellular Mechanisms ◽  
Germ Cell Specification ◽  
Vitro Model

AbstractMost humans carry a mixed population of mitochondrial DNA (mtDNA heteroplasmy) affecting ~1–2% of molecules, but rapid percentage shifts occur over one generation leading to severe mitochondrial diseases. A decrease in the amount of mtDNA within the developing female germ line appears to play a role, but other sub-cellular mechanisms have been implicated. Establishing an in vitro model of early mammalian germ cell development from embryonic stem cells, here we show that the reduction of mtDNA content is modulated by oxygen and reaches a nadir immediately before germ cell specification. The observed genetic bottleneck was accompanied by a decrease in mtDNA replicating foci and the segregation of heteroplasmy, which were both abolished at higher oxygen levels. Thus, differences in oxygen tension occurring during early development likely modulate the amount of mtDNA, facilitating mtDNA segregation and contributing to tissue-specific mutation loads.

scholarly journals Generation of Primordial Germ Cell-like Cells from iPSCs Derived from Turner Syndrome Patients

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3099
Author(s):  
Aline Fernanda de Souza ◽  
Fabiana Fernandes Bressan ◽  
Naira Caroline Godoy Pieri ◽  
Ramon Cesar Botigelli ◽  
Tamas Revay ◽  
...  
Keyword(s):  
Germ Cell ◽  
Turner Syndrome ◽  
Genetic Disorder ◽  
Primordial Germ Cells ◽  
Primordial Germ Cell ◽  
Cell Formation ◽  
In Vitro Models ◽  
Germline Development ◽  
Germ Cell Specification

Turner syndrome (TS) is a genetic disorder in females with X Chromosome monosomy associated with highly variable clinical features, including premature primary gonadal failure leading to ovarian dysfunction and infertility. The mechanism of development of primordial germ cells (PGCs) and their connection with ovarian failure in TS is poorly understood. An in vitro model of PGCs from TS would be beneficial for investigating genetic and epigenetic factors that influence germ cell specification. Here we investigated the potential of reprogramming peripheral mononuclear blood cells from TS women (PBMCs-TS) into iPSCs following in vitro differentiation in hPGCLCs. All hiPSCs-TS lines demonstrated pluripotency state and were capable of differentiation into three embryonic layers (ectoderm, endoderm, and mesoderm). The PGCLCs-TS recapitulated the initial germline development period regarding transcripts and protein marks, including the epigenetic profile. Overall, our results highlighted the feasibility of producing in vitro models to help the understanding of the mechanisms associated with germ cell formation in TS.

scholarly journals Induction of mouse germ-cell fate by transcription factors in vitro

Nature ◽  
2013 ◽  
Vol 501 (7466) ◽  
pp. 222-226 ◽  
Author(s):  
Fumio Nakaki ◽  
Katsuhiko Hayashi ◽  
Hiroshi Ohta ◽  
Kazuki Kurimoto ◽  
Yukihiro Yabuta ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Cell ◽  
Cell Fate

scholarly journals ZGLP1 is a determinant for the oogenic fate in mice

Science ◽  
2020 ◽  
Vol 367 (6482) ◽  
pp. eaaw4115 ◽  
Author(s):  
So I. Nagaoka ◽  
Fumio Nakaki ◽  
Hidetaka Miyauchi ◽  
Yoshiaki Nosaka ◽  
Hiroshi Ohta ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Reproductive Medicine ◽  
Zinc Fingers ◽  
Primordial Germ Cell ◽  
Transcriptional Regulator ◽  
Morphogenetic Protein ◽  
Underlying Mechanisms

Sex determination of germ cells is vital to creating the sexual dichotomy of germ cell development, thereby ensuring sexual reproduction. However, the underlying mechanisms remain unclear. Here, we show that ZGLP1, a conserved transcriptional regulator with GATA-like zinc fingers, determines the oogenic fate in mice. ZGLP1 acts downstream of bone morphogenetic protein, but not retinoic acid (RA), and is essential for the oogenic program and meiotic entry. ZGLP1 overexpression induces differentiation of in vitro primordial germ cell–like cells (PGCLCs) into fetal oocytes by activating the oogenic programs repressed by Polycomb activities, whereas RA signaling contributes to oogenic program maturation and PGC program repression. Our findings elucidate the mechanism for mammalian oogenic fate determination, providing a foundation for promoting in vitro gametogenesis and reproductive medicine.

scholarly journals Comparative Principles of DNA Methylation Reprogramming during Human and Mouse In Vitro Primordial Germ Cell Specification

2016 ◽  
Vol 39 (1) ◽  
pp. 104-115 ◽  
Author(s):  
Ferdinand von Meyenn ◽  
Rebecca V. Berrens ◽  
Simon Andrews ◽  
Fátima Santos ◽  
Amanda J. Collier ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Germ Cell ◽  
Primordial Germ Cell ◽  
Cell Specification ◽  
Germ Cell Specification ◽  
Human And Mouse

scholarly journals SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling

Development ◽  
2018 ◽  
Vol 145 (23) ◽  
pp. dev164160 ◽  
Author(s):  
Kentaro Mochizuki ◽  
Yukiko Tando ◽  
Tamotsu Sekinaka ◽  
Kei Otsuka ◽  
Yohei Hayashi ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Fate ◽  
Primordial Germ Cell ◽  
Bmp Signaling ◽  
Cell Fate Determination ◽  
Fate Determination ◽  
Mouse Primordial Germ Cell
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