[Relationships between the cell proliferation and the differentiation in the embryonic and larval intestine ofpleurodeles waltlii michah. II. Effects of intestinal chalones extracted from the intestine of the adult newt].

The intestinal chalones 1 and 2, extracted from the intestine of the adult newt, are known to inhibit the G1 and G2 phases of the cell cycle in the embryonic intestine. The effects of these intestinal chalones on the proliferation and differentiation of intestinal cells of newt embryos were studied with special attention to the dose-response relationship, the embryonic stage and the duration of treatment. The chalone 2 triggered a linear, dose-dependent inhibition between two concentration thresholds; nevertheless about 25% of the cycling cells were not inhibited either by the highest doses injected or by repeated injections. Sensitivity to chalone 2 appeared in the intestinal epithelium at the end of embryonic development (stage 34) but the cells were not delayed in the G2 phase for more than about 20 h in spite of repeated injections. It was inferred from the doseresponse curve of the mitotic inhibition by chalone 1, that the intestinal cell population was heterogeneous: about 50% of the cycling cells were inhibited by low concentrations of chalone 1; an additional proportion of about 25% of cycling cells was inhibited by 100 x more concentrated chalone 1 and the remaining 25% was insensitive to the inhibitor. Repeated injections of chalone 1 blocked about 50% of the cycling cells definitively in the G1 phase, speeded up digestion of yolk platelets, promoted the differentiation of goblet cells and depressed the number of stem cells in the proliferative compartment located beneath the epithelium. A kinetics model of cell proliferation and cell differentiation in the intestinal cell lineages was elaborated and it was suggested that the arrest of mitotic activity and the completion of differentiation in an embryonic cell depends on two incoming signals: one is intracellular and appears when the required number of cell cycles has occured in the cell lineage, leading to a committed stem cell sufficiently differentiated to synthesise chalone and to respond to chalone; the other signal is extracellular and appears when the chalone concentration is high enough: i.e. when the required number of cells is obtained in this tissue.