Nr5a2, an orphan nuclear receptor, is a key regulator in early embryonic development and has implications in disease. In early embryogenesis, it plays roles in zygotic genome activation (ZGA) and lineage segregation, connecting ZGA to the first lineage segregation in totipotent embryos. It is also involved in regulating genes related to pluripotency and early lineage specification, and is essential for the development of certain tissues like those in the jaw [1,2,4].

Mouse models have been crucial in understanding Nr5a2's functions. Nr5a2 -/- embryos arrest at the early morula stage, exhibit altered lineage specification, mitotic failure, and chromosome segregation defects. Despite a minor role in ZGA, it predominantly acts as a master regulator at the eight-cell stage, controlling expression of lineage-specifying transcription factors and genes involved in mitosis, telomere maintenance, and DNA repair. Also, Nr5a2 ablation leads to blastocysts lacking inner cell mass (ICM), indicating its importance in first lineage differentiation [3,6]. In pancreatic cancer, genetic silencing or inhibition of NR5A2 in models using primary PDAC cells and CSC-enriched sphere cultures shows it plays a dual role: promoting cell proliferation in differentiated cancer cells and enhancing stemness in cancer stem cells. Inhibiting NR5A2 with Cpd3 sensitizes PDAC models to standard chemotherapy [5].

In summary, Nr5a2 is essential for early embryonic development, coordinating proliferation, genome stability, and lineage specification. In disease, especially pancreatic cancer, Nr5a2 has cell-context dependent effects, and its inhibition shows promise in restoring chemosensitivity. Mouse models, especially Nr5a2 KO models, have been instrumental in revealing these functions, providing insights into both normal development and disease mechanisms [3,5,6].

References:

1. Lai, Fangnong, Li, Lijia, Hu, Xiaoyu, Li, Jinsong, Xie, Wei. 2023. NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos. In Cell research, 33, 952-966. doi:10.1038/s41422-023-00887-z. https://pubmed.ncbi.nlm.nih.gov/37935903/

2. Gassler, Johanna, Kobayashi, Wataru, Gáspár, Imre, Ladstätter, Sabrina, Tachibana, Kikuë. 2022. Zygotic genome activation by the totipotency pioneer factor Nr5a2. In Science (New York, N.Y.), 378, 1305-1315. doi:10.1126/science.abn7478. https://pubmed.ncbi.nlm.nih.gov/36423263/

3. Festuccia, Nicola, Vandormael-Pournin, Sandrine, Chervova, Almira, Cohen-Tannoudji, Michel, Navarro, Pablo. 2024. Nr5a2 is dispensable for zygotic genome activation but essential for morula development. In Science (New York, N.Y.), 386, eadg7325. doi:10.1126/science.adg7325. https://pubmed.ncbi.nlm.nih.gov/39361745/

4. Chen, Hung-Jhen, Barske, Lindsey, Talbot, Jared C, Tucker, Abigail S, Crump, J Gage. 2023. Nuclear receptor Nr5a2 promotes diverse connective tissue fates in the jaw. In Developmental cell, 58, 461-473.e7. doi:10.1016/j.devcel.2023.02.011. https://pubmed.ncbi.nlm.nih.gov/36905926/

5. Zheng, Quan, Tang, Jiajia, Aicher, Alexandra, Sancho, Patricia, Heeschen, Christopher. 2023. Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity. In Journal of experimental & clinical cancer research : CR, 42, 323. doi:10.1186/s13046-023-02883-y. https://pubmed.ncbi.nlm.nih.gov/38012687/

6. Zhao, Yanhua, Zhang, Meiting, Liu, Jiqiang, Li, Jingyu, Lei, Lei. 2024. Nr5a2 ensures inner cell mass formation in mouse blastocyst. In Cell reports, 43, 113840. doi:10.1016/j.celrep.2024.113840. https://pubmed.ncbi.nlm.nih.gov/38386558/