A Positive Regulatory Loop between foxi3a and foxi3b Is Essential for Specification and Differentiation of Zebrafish Epidermal Ionocytes

Abstract

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.

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

“…For double-label in situ hybridization, igfbp5a, 14 trpv5/6, 11 and atp6v1al 17 riboprobes were labeled with either DIG or dinitrophenol following the published protocol. 55 Fluorescent images were acquired using a Leica TCS SP5 confocal microscope with the Leica LAS AF software.…”

Ion uptake and acid secretion in zebrafish (Danio rerio)

“…Indeed, it was also found that not all ECaC-expressing cells coexpressed both zPMCA2 and zNCX1b in zebrafish gill NaR cell populations (Liao et al, 2007), which may be analogous to trout PNA + cells (see below). Fish gill cells that express only one or two (never all) of the three major Ca 2+ transporters may be in the process of terminal differentiation as Hsiao and coworkers (Hsiao et al, 2007) reported in zebrafish embryonic skin ionocytes. Alternatively, the Ca 2+ transporter(s) expressed in these cells may be involved in intracellular Ca 2+ homeostasis or other cellular events (Prasad et al, 2007;Reppel et al, 2007), and this needs to be clarified in further investigations.…”

mab21-l3 regulates cell fate specification of multiciliate cells and ionocytes

“…Both cells are essential for human physiological processes, and malformation of them is associated with human diseases, including bronchiectasis, hydrocephalus and distal tubule acidosis 1,2 . Cell fate specifications of MCCs and ionocytes are known to be suppressed by the Notch pathway in various developing epithelia [5][6][7][8][9][10][11][12][13][14] . However, MCCspecific and ionocyte-specific transcriptional programmes are governed by different master regulators: a coiled-coil protein multicilin 15 and a forkhead transcription factor foxj1 (refs [16][17][18] for MCCs and another forkhead transcription factor foxi1 (refs 7-9,19-21) for ionocytes.…”