Lithium inhibits morphogenesis of the nervous system but not neuronal differentiation in Xenopus laevis

Abstract

Xenopus embryos treated with 100 mM-lithium from the 2- to 4-cell stage to the early blastula stage (4h) failed to neurulate and developed without a discernible anteroposterior axis. The internal structure of defective embryos was grossly disorganized, but immunohistochemical staining with cell-type-specific antibodies revealed differentiated nerve and muscle cells. Quantitative assay in tissue cultures from control and acutely abnormal lithium-treated embryos showed that neural differentiation was enhanced and muscle differentiation unaffected. The embryos took up about 0.5 mM-lithium at threshold, maximal effects resulted at 2–3 mM. Most of the lithium was extruded from the cells into the blastocoel fluid, where lithium reached 17 mM. The threshold intracellular concentration was about 150 microM. Lithium uptake rose steeply as the osmotic/ionic strength of the bathing medium increased. Sodium, potassium and lithium were equally able to increase the permeability of the embryo. However, sodium ions enhanced, while potassium ions interfered with, the uptake of lithium. Treatment with lithium at progressively later stages reduced the developmental defects and neural differentiation returned to normal levels. The uptake of lithium did not decline concomitantly. We conclude that lithium does not inhibit neural induction, but interferes with dorsal patterning. The sensitivity of the embryo to lithium is determined by developmental stage. The very low, effective intracellular concentrations may be important in understanding the mechanism of lithium-generated defects.