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.

Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an NRF2 mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2.

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Oestrogen-related receptor a (ERRa) is an orphan nuclear receptor which is important for adaptive metabolic responses under conditions of increased energy demand, such as cold, exercise and fasting. Importantly, metabolism under these conditions is usually accompanied by elevated production of organic acids, which may threaten the body acid-base status. Although ERRa is known to help regulate ion transport by the renal epithelia, its role in the transport of acid-base equivalents remains unknown. Here, we tested the hypothesis that ERRa is involved in acid-base regulation mechanisms by using zebrafish as the model to examine the effects of ERRa on transepithelial H þ secretion. ERRa is abundantly expressed in H þ -pump-rich cells (HR cells), a group of ionocytes responsible for H þ secretion in the skin of developing embryos, and its expression is stimulated by acidic (pH 4) environments. Knockdown of ERRa impairs both basal and low pH-induced H þ secretion in the yolk-sac skin, which is accompanied by decreased expression of H þ -secreting-related transporters. The effect of ERRa on H þ secretion is achieved through regulating both the total number of HR cells and the function of individual HR cells. These results demonstrate, for the first time, that ERRa is required for transepithelial H þ secretion for systemic acid-base homeostasis.

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Background: Cephalopods have evolved strong acid-base regulatory abilities to cope with CO 2 induced pH fluctuations in their extracellular compartments to protect gas transport via highly pH sensitive hemocyanins. To date, the mechanistic basis of branchial acid-base regulation in cephalopods is still poorly understood, and associated energetic limitations may represent a critical factor in high power squids during prolonged exposure to seawater acidification. Results: The present work used adult squid Sepioteuthis lessoniana to investigate the effects of short-term (few hours) to medium-term (up to 168 h) seawater acidification on pelagic squids. Routine metabolic rates, NH 4 + excretion, extracellular acid-base balance were monitored during exposure to control (pH 8.1) and acidified conditions of pH 7.7 and 7.3 along a period of 168 h. Metabolic rates were significantly depressed by 40% after exposure to pH 7.3 conditions for 168 h. Animals fully restored extracellular pH accompanied by an increase in blood HCO 3 − levels within 20 hours. This compensation reaction was accompanied by increased transcript abundance of branchial acid-base transporters including V-type H +-ATPase (VHA), Rhesus protein (RhP), Na + /HCO 3 − cotransporter (NBC) and cytosolic carbonic anhydrase (CAc). Immunocytochemistry demonstrated the sub-cellular localization of Na + /K +-ATPase (NKA), VHA in basolateral and Na + /H +-exchanger 3 (NHE3) and RhP in apical membranes of the ion-transporting branchial epithelium. Branchial VHA and RhP responded with increased mRNA and protein levels in response to acidified conditions indicating the importance of active NH 4 + transport to mediate acid-base balance in cephalopods. Conclusion: The present work demonstrated that cephalopods have a well developed branchial acid-base regulatory machinery. However, pelagic squids that evolved a lifestyle at the edge of energetic limits are probably more sensitive to prolonged exposure to acidified conditions compared to their more sluggish relatives including cuttlefish and octopods.