Phase transition specified by a binary code patterns the vertebrate eye cup.

The developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE), and the ciliary margin (CM). By single-cell analysis, we showed that fibroblast growth factor (FGF) signaling regulates the CM in its stem cell­like property of self-renewal, differentiation, and survival, which is balanced by an evolutionarily conserved Wnt signaling gradient. FGF promotes Wnt signaling in the CM by stabilizing ß-catenin in a GSK3ß-independent manner. While Wnt signaling converts the NR to either the CM or the RPE depending on FGF signaling, FGF transforms the RPE to the NR or CM dependent on Wnt activity. The default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in human retinal organoid. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling.

Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling.

The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during lacrimal gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal-regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the lacrimal gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of lacrimal gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of lacrimal gland development.

Mechanisms of an increased level of serum iron in gamma-irradiated mice.

The potential mechanisms underlying the increase in serum iron concentration in gamma-irradiated mice were studied. The gamma irradiation dose used was 4 Gy, and cobalt-60 ((60)Co) source was used for the irradiation. The dose rate was 0.25 Gy/min. In the serum of irradiated mice, the concentration of ferrous ions decreased, whereas the serum iron concentration increased. The concentration of ferrous ions in irradiated mice returned to normal at 21 day post-exposure. The concentration of reactive oxygen species in irradiated mice increased immediately following irradiation but returned to normal at 7 day post-exposure. Serum iron concentration in gamma-irradiated mice that were pretreated with reduced glutathione was significant lower (p < 0.01) than that in mice exposed to gamma radiation only. However, the serum iron concentration was still higher than that in normal mice (p < 0.01). This change was biphasic, characterized by a maximal decrease phase occurring immediately after gamma irradiation (relative to the irradiated mice) and a recovery plateau observed during the 7th and 21st day post-irradiation, but serum iron recovery was still less than that in the gamma-irradiated mice (4 Gy). In gamma-irradiated mice, ceruloplasmin activity increased and serum copper concentration decreased immediately after irradiation, and both of them were constant during the 7th and 21st day post-irradiation. It was concluded that ferrous ions in irradiated mice were oxidized to ferric ions by ionizing radiation. Free radicals induced by gamma radiation and ceruloplasmin mutually participated in this oxidation process. The ferroxidase effect of ceruloplasmin was achieved by transfer of electrons from ferrous ions to cupric ions.

Development of serum zinc as a biological dosimeter in mice.

PURPOSE: To develop a new biological dosimeter based on serum zinc concentration. MATERIALS AND METHODS: Male mice (8 weeks old) were exposed to different doses (0, 1.0, 2.0, 4.0, or 8.0 Gy) of gamma rays from a (60)Co source. Blood was then collected from the orbital area of these mice, and the serum zinc concentration was detected using the 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol colorimetric method. The data were analyzed using one-way analysis of variance. RESULTS: The serum zinc concentration in the irradiated mice decreased with increasing dose. Two dose-response relationships fitted to the linear quadratic curve were obtained: One immediately after exposure (y = 0.010x(2) - 0.133x + 0.663, r = 0.983) and the other on the seventh day after exposure (y = 0.008x(2) - 0.127x + 0.695, r = 0.990). The serum zinc concentration continued to decrease until 21 days after exposure. The absorbed doses estimated using both dose-response relationships were close to the actual doses. CONCLUSIONS: Serum zinc is a quick, effective, and sensitive biomarker for early biological doses assessment of mice irradiated by gamma radiation.

Development of serum copper-based biological dosimetry in whole body gamma irradiation of mice.

A new biological dosimeter based on serum copper has been developed. Serum copper in mice subjected to a 60Co source at a dose rate of 0.5 Gy min-1 was detected using the bis(cyclohexanone) oxaldihydrazone colorimetric method. The dose range was from 0.5­7 Gy. The results demonstrate that serum copper decreases with increasing dose. A linear dose response is obtained. The detection limit based on serum copper is the same as that with the lower limit of dose assessment; i.e., about 1 Gy. The decrease in serum copper continues until the 28th day after gamma radiation. The absorbed doses in mice assessed using the linear curve are close to "blind" doses of 4 and 6 Gy. Therefore, serum copper is a quick, simple, and accurate biomarker for early assessment of radiation exposure of mice in the range of 0.5­7 Gy.