Programming of pluripotency and the germ line co-evolved from a Nanog ancestor

Crowley, Darren; Simpson, Luke; Chatfield, Jodie; Forey, Teri; Allegrucci, Cinzia; Sang, Fei; Holmes, Nadine; Genikhovich, Grigory; Technau, Ulrich; Cunningham, Doreen; Silva, Elena; Mullin, Nicholas; Dixon, James E; Loose, Matthew; Alberio, Ramiro; Johnson, Andrew D

Abstract

Francois Jacob proposed that evolutionary novelty arises through incremental tinkering with pre-existing genetic mechanisms. Vertebrate evolution was predicated on pluripotency—the ability of embryonic cells to form somatic germ-layers and primordial germ cells (PGCs). The origins of pluripotency remain unclear, as key regulators like Nanog, are not conserved outside of vertebrates. Given its role in mammalian development, we hypothesized that NANOG activity might exist in ancestral invertebrate genes. Here we find that Vent from the hemichordate Saccoglossus kowalevskii exhibits NANOG activity, programming pluripotency in Nanog-/- mouse pre-iPS cells and NANOG-depleted axolotl embryos. Vent from the cnidarian Nematostella vectensis showed partial activity, while Vent from sponges and vertebrates had no activity. VENTX knockdown in axolotls revealed a role in germ-line competent mesoderm, which Saccoglossus Vent could rescue, but Nematostella Vent could not. This suggests the last deuterostome ancestor had a Vent gene capable of programming pluripotency and germ-line competence.

Citation

Crowley, D., Simpson, L., Chatfield, J., Forey, T., Allegrucci, C., Sang, F., Holmes, N., Genikhovich, G., Technau, U., Cunningham, D., Silva, E., Mullin, N., Dixon, J. E., Loose, M., Alberio, R., & Johnson, A. D. (2025). Programming of pluripotency and the germ line co-evolved from a Nanog ancestor. Cell Reports, 44(3), Article 115396. https://doi.org/10.1016/j.celrep.2025.115396

• Journal Article Type: Article
• Acceptance Date: Feb 13, 2025
• Online Publication Date: Mar 8, 2025
• Publication Date: Mar 25, 2025
• Deposit Date: Feb 25, 2025
• Publicly Available Date: Mar 9, 2026
• Journal: Cell Reports
• Print ISSN: 2211-1247
• Electronic ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 44
• Issue: 3
• Article Number: 115396
• DOI: https://doi.org/10.1016/j.celrep.2025.115396
• Keywords: pluripotency; nanog; vent; germline; vertebrate; evolution; mesoderm; iPSC; hemichordates; mouse embryonic stem cells
• Public URL: https://nottingham-repository.worktribe.com/output/45854678
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2211124725001676