OTX2 is a transcription factor that functions as a critical regulator of early mammalian development and embryonic genome activation. In humans, OTX2 is maternally provided and acts as a PRD-like homeobox transcription factor essential for proper embryonic genome activation (EGA) beginning at the four-cell stage 1. OTX2 directly binds promoters and enhancers of key EGA genes including TPRX1 and TPRX2, promoting chr14 accessibility and activation of early developmental genes 1. The gene is also enriched at sites of 5-hydroxymethylcytosine modification and regulates early lineage gene expression during preimplantation development 2. Beyond EGA, OTX2 functions in formative pluripotency transitions, where it serves as a critical dependency factor for stem cell maintenance and lineage competency 3. OTX2 participates in establishing the anterior-posterior axis during post-implantation development and guides epiblast patterning through DKK1/OTX2 interactions 4. Clinically, OTX2 mutations cause combined pituitary hormone deficiency and syndromic microphthalmia 5. OTX2 also functions in the mouth gene program conserved across animal evolution 6. Aberrant OTX2 function appears linked to Group 4 medulloblastoma, where OTX2 knockdown relieves differentiation blockade in cerebellar progenitors 7.