BackgroundEpidermal ionocytes play essential roles in the transepithelial transportation of ions, water, and acid-base balance in fish embryos before their branchial counterparts are fully functional. However, the mechanism controlling epidermal ionocyte specification and differentiation remains unknown.Methodology/Principal FindingsIn zebrafish, we demonstrated that Delta-Notch-mediated lateral inhibition plays a vital role in singling out epidermal ionocyte progenitors from epidermal stem cells. The entire epidermal ionocyte domain of genetic mutants and morphants, which failed to transmit the DeltaC-Notch1a/Notch3 signal from sending cells (epidermal ionocytes) to receiving cells (epidermal stem cells), differentiates into epidermal ionocytes. The low Notch activity in epidermal ionocyte progenitors is permissive for activating winged helix/forkhead box transcription factors of foxi3a and foxi3b. Through gain- and loss-of-function assays, we show that the foxi3a-foxi3b regulatory loop functions as a master regulator to mediate a dual role of specifying epidermal ionocyte progenitors as well as of subsequently promoting differentiation of Na+,K+-ATPase-rich cells and H+-ATPase-rich cells in a concentration-dependent manner.Conclusions/SignificanceThis study provides a framework to show the molecular mechanism controlling epidermal ionocyte specification and differentiation in a low vertebrate for the first time. We propose that the positive regulatory loop between foxi3a and foxi3b not only drives early ionocyte differentiation but also prevents the complete blockage of ionocyte differentiation when the master regulator of foxi3 function is unilaterally compromised.

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Animals make use of changes in photoperiod to adapt their physiology to the forthcoming breeding season. Comparative studies have contributed to our understanding of the mechanisms of seasonal reproduction in vertebrates. Birds are excellent models for studying these phenomena because of their rapid and dramatic responses to changes in photoperiod. Deep brain photoreceptors in birds perceive and transmit light information to the pars tuberalis (PT) in the pituitary gland, where the thyroid-stimulating hormone (TSH) is produced. This PT-TSH locally increases the level of the bioactive thyroid hormone T3 via the induction of type 2 deiodinase production in the mediobasal hypothalamus, and an increased T3 level, in turn, controls seasonal gonadotropin-releasing hormone secretion. In mammals, the eyes are the only photoreceptive structure, and nocturnal melatonin secretion encodes day-length information and regulates the PT-TSH signaling cascade. In Salmonidae, the saccus vasculosus plays a pivotal role as a photoperiodic sensor. Together, these studies have uncovered the universality and diversity of fundamental traits in vertebrates.