Mucus secretion and ciliary motility are hallmarks for muco-ciliary epithelia (MCE). Both, mammalian airways as well as the less complex epidermis of Xenopus embryos show cilia-driven mucus flow to protect the organism against harmful effects by exogenous pathogens or pollutants. Four cell types set up the epidermal MCE in Xenopus. Multi-ciliated cells (MCCs) generate an anterior to posterior flow of mucus. Ion secreting cells (ISCs) are characterized by the expression of ion transporters, presumably to maintain a favorable homeostasis. The largest cell type is represented by goblet cells, which cover most of the epidermis and exhibit secretory properties. Additionally, small secretory cells (SSCs) release mucus, antibiotic compounds, and the monoamine serotonin (5-hydroxytryptamine; 5-HT). We have recently shown that serotonin regulates flow velocity by acting on ciliary beat frequency. Here, we describe the identification and functional characterization of Xenopus polka-dots (Xpod). No homologous genes or proteins were found in other vertebrates, including Xenopus tropicalis. We demonstrate that Xpod serves as an SSC-specific marker, starting to be expressed shortly after SSC specification at neurula stages. Overexpression of a tagged Xpod protein resulted in the localization of secretory granules. Notch signaling induced SSC cell fate, in contrast to its repressing effect on MCC and ISC specification. Xpod loss-of-function revealed that mucus and 5-HT release by SSCs was severely diminished, which impaired the ciliary beating of MCCs. In summary, Xpod specifically marked SSCs and was required for muco-ciliary secretion in Xenopus laevis., (© 2019 The Authors. Genesis published by Wiley Periodicals, Inc.)