Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells

Hayashi, Kozaburo; Ohta, Hiroshi; Kurimoto, Kazuki; Aramaki, Shigeto; Saitou, Mitinori

doi:10.1016/j.cell.2011.06.052

Cited by 1,184 publications

(1,733 citation statements)

References 53 publications

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“…It is noteworthy that subpopulations of ESC cultures have been proposed to bear a similar character to primed pluripotent cells and vice versa (Hayashi et al , 2008; Han et al , 2010). Upon differentiation, naïve ESCs transit through a state (named EpiLCs) with transcriptional similarity to the early post‐implantation epiblast (Buecker et al , 2010; Hayashi et al , 2011). Esrrb‐GFP negative cells and EpiLCs have a high correlation in OCT4 chromatin binding (Pearson's r = 0.60).…”

Section: Discussionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

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Section: Discussionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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“…Under the microscope, Sertoli cells were fibroblast-like and attached to the culture plates, while spermatogonia were round in shape in the suspension or adhered slightly to the plates. Flow cytometry analysis revealed that ,93% of the GFP-positive cells were integrin-beta3 (marker for primordial germ cell 18 ) positive, suggesting that the green cells were indeed spermatogonia.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of Col1a1 induces differentiation in mouse spermatogonia

Chen¹,

Li²,

Xu³

2012

Asian J Androl

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Col1a1 (one of the subunit of collagen type I) is a collagen, which belongs to a family of extracellular matrix (ECM) proteins that play an important role in cellular proliferation and differentiation. However, the role of Col1a1 in spermatogenesis, especially in the control of proliferation and differentiation of spermatogonial stem cells (SSCs), remains unknown. In this study, we explored effects of downregulation of Col1a1 on differentiation and proliferation of mouse spermatogonia. Loss-of-function study revealed that Oct4 and Plzf, markers of SSC self-renewal, were significantly decreased, whereas the expression of c-kit and haprin, hallmarks of SSC differentiation, was enhanced after Col1a1 knockdown. Cell cycle analyses indicated that two-thirds of spermatogonia were arrested in S phase after Col1a1 knockdown. In vivo experiments, DNA injection and electroporation of the testes showed that spermatogonia self-renewal ability was impaired remarkably with the loss-of-function of Col1a1. Our data suggest that silencing of Col1a1 can suppress spermatogonia self-renewal and promote spermatogonia differentiation.

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“…Moreover, when transplanted into younger, 5–10 day old recipients, not only primordial germ cells from all foetal ages, but also epiblasts from 6.5 dpc embryos could colonise and go on to produce spermatozoa (Chuma et al ., 2005). Taking this to extreme levels, it is now possible (but challenging and with poor efficiency) to generate PGC‐like cells from ES cells and transplant these into host testes to produce spermatids and live mice through assisted reproduction techniques (Hayashi et al ., 2011). …”

Section: Germ Cellsmentioning

confidence: 99%

Cell‐specific ablation in the testis: what have we learned?

2015

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SummaryTesticular development and function is the culmination of a complex process of autocrine, paracrine and endocrine interactions between multiple cell types. Dissecting this has classically involved the use of systemic treatments to perturb endocrine function, or more recently, transgenic models to knockout individual genes. However, targeting genes one at a time does not capture the more wide‐ranging role of each cell type in its entirety. An often overlooked, but extremely powerful approach to elucidate cellular function is the use of cell ablation strategies, specifically removing one cellular population and examining the resultant impacts on development and function. Cell ablation studies reveal a more holistic overview of cell–cell interactions. This not only identifies important roles for the ablated cell type, which warrant further downstream study, but also, and importantly, reveals functions within the tissue that occur completely independently of the ablated cell type. To date, cell ablation studies in the testis have specifically removed germ cells, Leydig cells, macrophages and recently Sertoli cells. These studies have provided great leaps in understanding not possible via other approaches; as such, cell ablation represents an essential component in the researchers’ tool‐kit, and should be viewed as a complement to the more mainstream approaches to advancing our understanding of testis biology. In this review, we summarise the cell ablation models used in the testis, and discuss what each of these have taught us about testis development and function.

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Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells

Cited by 1,184 publications

References 53 publications

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Downregulation of Col1a1 induces differentiation in mouse spermatogonia

Cell‐specific ablation in the testis: what have we learned?

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