Cortisol promotes differentiation of epidermal ionocytes through Foxi3 transcription factors in zebrafish (Danio rerio)

Glucocorticoid regulates epidermal cell proliferation, and is used to treat certain skin disorders. Cortisol, a glucocorticoid, is also linked to skin development in teleost fish. Cortisol increases the number of epithelial ionocytes during environmental acclimation in euryhaline fishes, but it is unclear whether this is due to increased differentiation or proliferation. To investigate, we treated zebrafish embryos with exogenous cortisol (20 mg/L). The densities of the ionocytes Na+-K+-ATPase rich cells (NaRCs) and H+-ATPase rich cells (HRCs) were significantly increased by cortisol, and this was accompanied by an increase in the respective marker genes. Expression of the glucocorticoid receptor (GR) gene was decreased. Cortisol treatment also increased ionocytes in cultured adult zebrafish gills, and up-regulated expression of genes encoding forkhead box I3 (foxi3a and foxi3b) transcription factors, which regulate ionocyte progenitor development. GR expression was up-regulated by cortisol in vitro; as such, the observed decrease in vivo reflects a regulatory systemic-negative feedback. Notably, in situ hybridization revealed that foxi3a/b mRNA expression was increased by cortisol at 24-48 h post-fertilization. Cortisol also decreased keratinocytes, but did not affect epidermal stem cells or mucus cells. We conclude that foxi3a/b transactivation by cortisol-GR favors differentiation of ionocyte progenitors, thereby facilitating proliferation of mature ionocytes.