A transcription factor toggle switch determines differentiated epidermal cell identities in Hydra.

In Hydra, a simple cnidarian model, epithelio-muscular cells shape and maintain body architecture through continuous renewal. Undifferentiated cells from the mid-body region migrate passively toward the extremities, replacing shed cells and acquiring region-specific identities. This ongoing turnover, together with Hydra's stable axial organization, provides a powerful model to study how cell type specification is integrated with body patterning. Yet, the molecular mechanisms that govern epithelial identity remain largely unknown. Here, we identify a double-negative feedback loop between the transcription factors Zic4 and Gata3 that functions as a toggle switch to control terminal epidermal cell fates. Zic4, activated by Wnt signaling from the head organizer, induces battery cell specification in tentacles. In contrast, Gata3 promotes basal disk cell identity at the aboral end. These factors are mutually repressive: silencing one leads to expansion of the other's domain and ectopic cell fate induction. Notably, simultaneous knockdown of both restores normal patterning, suggesting that identity is dictated by their relative balance rather than absolute levels. Our study reveals how opposing transcriptional signals coordinate epithelial identity with axial patterning at Hydra's poles.