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Transcription Factor Combo Drives Oocyte Production from Mouse ESCs

Review of "Reconstitution of the oocyte transcriptional network with transcription factors" from Nature by Stuart P. Atkinson

The differentiation of oocytes from mouse female primordial germ cells occurs through concurrent oocyte growth and meiosis. Dynamic alterations to gene expression trigger oocyte growth during the transition from primordial to primary follicle [1], with the expression of a small group of genes, including Lhx8 [2], Nobox [3], and Tbp2 [4], essential to this process. However, we lacked a comprehensive description and functional investigation of the gene regulatory network specifically orchestrating oocyte growth.

Now, researchers led by Nobuhiko Hamazaki and Katsuhiko Hayashi (Kyushu University, Fukuoka, Japan) describe how a combination of eight transcription factors orchestrate oocyte growth and report the conversion of mouse embryonic stem cells into oocyte-like cells via their forced expression [5].

The authors evaluated gene expression by RNA sequencing in an in vitro mouse oocyte development system that differentiates embryonic stem cells into primordial germ cell-like cells, which then undergo oogenesis in the presence of supporting gonadal somatic cells to give rise to oocytes [6]. This setup allowed the identification of transcription-related genes associated with oocyte development, and additional functional screening by loss-of-function analysis in embryonic stem cells highlighted the general importance of eight transcription factor proteins - LHX8, SOHLH1, NOBOX, TBPL2, STAT3, DYNLL1, SUB1, and FIGLA.

Excitingly, the forced expression of this group of eight transcription factors induced the rapid conversion of embryonic stem cells into oocyte-like cells, which could be fertilized by sperm and divided until they hit the eight-cell stage of embryonic development without the need for primordial germ cell specification.

The authors posit that their directly induced oocyte-like cells (or "DIOLs") may represent a means to produce large amounts of oocyte cytoplasm (or ooplasm), a material with possible applications in assisted reproduction (e.g., mitochondrial replacement therapy) and somatic cell nuclear transfer. However, future research into the induction of meiosis in DIOLs may open other exciting research avenues.

For more on how a transcription factor combo can induce the generation of oocyte-like cells from pluripotent stem cells and their potential uses, stay tuned to the Stem Cells Portal!


References

  1. Pan H, O'Brien MJ, Wigglesworth K, et al., Transcript profiling during mouse oocyte development and the effect of gonadotropin priming and development in vitro. Developmental Biology 2005;286:493-506.
  2. Pangas SA, Choi Y, Ballow DJ, et al., Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proceedings of the National Academy of Sciences 2006;103:8090.
  3. Rajkovic A, Pangas SA, Ballow D, et al., NOBOX Deficiency Disrupts Early Folliculogenesis and Oocyte-Specific Gene Expression. Science 2004;305:1157.
  4. Gazdag E, Santenard A, Ziegler-Birling C, et al., TBP2 is essential for germ cell development by regulating transcription and chromatin condensation in the oocyte. Genes & Development 2009;23:2210-2223.
  5. Hamazaki N, Kyogoku H, Araki H, et al., Reconstitution of the oocyte transcriptional network with transcription factors. Nature 2021;589:264-269.
  6. Hikabe O, Hamazaki N, Nagamatsu G, et al., Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature 2016;539:299-303.