Complex epithelia have multiple functions, including the regulation of ion transport and homeostasis. A failure to regulate ionic homeostasis is a hallmark of many human diseases. For example, defects in the function of epithelia whose primary function is ion transport, such as those found in kidney and epididymis, lead to abnormalities such as distal renal acidosis and male sterility. In addition, although ion transport is not the primary function of other epithelia, such as the secretory and mucociliary epithelia found in the gut and lung, ionic regulation is crucial for their normal function. In diseases such as cystic fibrosis, failure of ionic regulation is associated with abnormalities in mucus consistency and secretion, which has deleterious effects in the gut and lungs.
Most epithelia consist of several cell types, including specialised cells dedicated to ionic regulation (known as ionocytes, mitochondria-rich cells, proton-secreting cells or intercalated cells). Challenges in understanding disorders of epithelial ion homeostasis include understanding how the different cell types cooperate to form a functional organ and how abnormalities in one cell type can affect the function of other cell types. However, owing to the difficulties in studying epithelia in vivo in mammals, there is an urgent need for model systems that recapitulate the complexity of the epithelia yet still enable experimental observation and manipulation.
The frog embryonic (larval) skin, which contains both mucus-secreting goblet cells and multiciliated cells, has been used as a model system for mucociliary epithelia of the lung, particularly to understand the molecular mechanisms of ciliogenesis. Here, the authors show that the epidermis of Xenopus tropicalis larvae also contains a population of ionocytes in addition to mucus-secreting goblet cells and multiciliated cells. They show that the ionocytes express proteins that modulate ion homeostasis, such as v-atpase, carbonic anhydrase 12, pendrin and monocarboxylate transporter 4, and intercalate from the inner to the outer layer of the epidermis. Furthermore, X. tropicalis ionocyte development depends on the transcription factor foxi1e, indicating that they are highly similar to the intercalated cells found in the mammalian kidney. Knockdown of foxi1e expression prevents the development of ionocytes, which, surprisingly, has a deleterious effect on the development of multiciliated cells, which show fewer and aberrantly beating cilia.
Implications and future directions
This work demonstrates for the first time the influence of ionocytes on ciliated cells in an in vivo system, and expands the utility of Xenopus larval skin as a versatile model for the study of secretory, transporting and mucociliary epithelia in vivo. Combined with other advantages of Xenopus as a model (amenability to live imaging and manipulation of gene expression, as well as a fully sequenced genome), this represents a powerful system in which to examine how different cell types interact to form a functional organ, to model complex epithelial diseases and to test potential therapies.
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