Nr5a2, an orphan nuclear receptor, is a key transcription factor [2]. It plays essential roles in early embryonic development, connecting zygotic genome activation (ZGA) to the first lineage segregation [1]. It binds to its motif within SINE B1/Alu retrotransposable elements in cis-regulatory regions of ZGA genes, promoting chromatin accessibility during ZGA [2]. In addition, it is involved in cell-fate decisions in the jaw, pancreatic cancer stemness regulation, and inner cell mass formation in mouse blastocysts [4,5,6].

In mouse models, Nr5a2-deficient embryos develop beyond the 2-cell stage with largely activated zygotic genomes but arrest at the morula stage. 4-8C-specific gene activation is impaired, and there are altered lineage specification, mitotic failure, and chromosome segregation defects [1,3]. In pancreatic cancer, genetic silencing or inhibition of NR5A2 disrupts stemness by interfering with SOX2/MYC signaling and restores chemosensitivity [4]. In the jaw, Nr5a2 mutants in zebrafish and neural-crest-specific Nr5a2 loss in mice lead to skeletal, tendon, and salivary gland defects [5]. In mouse blastocysts, Nr5a2 ablation results in blastocysts lacking inner cell mass [6].

In summary, Nr5a2 is crucial for early embryonic development, cell-fate determination in the jaw, and plays a role in pancreatic cancer. Gene knockout mouse models have been instrumental in revealing its functions in these biological processes and disease conditions, providing insights into the underlying mechanisms and potential therapeutic targets.