A proposed model for Klf4 functions in maintaining the <i>dlc</i>^<i>+</i> ionocyte progenitor population.

Zebrafish Klf4 exerts two-level regulatory activity toward the development of ionocytes. In wild-type embryos, Klf4 represses p53 expression, preventing the induction of cdkn1a/p21, and thereby allowing proper p63+ epidermal stem cell proliferation (box 1). At a second level, Klf4 acts as a repressor, regulating Dlc-mediated lateral inhibition by binding to the dlc promoter to maintain proper dlc+ ionocyte progenitor population and patterning during the initiation of ionocyte progenitor differentiation (box 2). The output patterns are illustrated in 2D cell schematics, and representative images of dlc mRNA in situ hybridization from klf4 morphants, wild-type and klf4-overexpressing embryos at bud stage are shown in box 3. Under klf4 deficiency, p53 expression is no longer repressed and cdkn1a/p21 is activated, which results in reduced proliferation of p63+ epidermal stem cell and larger/fewer dlc+ progenitors after selection by lateral inhibition (box 3.1). When klf4 is overexpressed (box 3.3), more stem cells are selected as ionocyte progenitors and dlc+ progenitor clusters develop.