Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens.

Abstract

In the small intestine and colon, administration of mutagens leads to the emergence of crypts populated by cells with a different, mutated phenotype. This is preceded by a transient rise in the frequency of crypts with a partially mutated phenotype, and the disappearance of these partially mutated crypts occurs contemporaneously with the attainment of a plateau value of the wholly mutated crypts. Here, using the mutagen ethyl nitrosourea and loss of glucose-6-phosphate dehydrogenase staining as a marker, we show that the plateau is reached at between 4.6 and 7 weeks in the colon and at 12 weeks in the small intestine of the same mice. Explanations for this difference have included differences in the stem cell cycle time of a single "master" stem cell or multiple stem cells occupying a stem cell "niche" with random loss after stem cell division. However, we demonstrate that the crypt fission index, or the incidence of crypts in fission, is some four times higher in the colon than in the small intestine at the time of ethyl nitrosourea injection, and propose an alternative hypothesis based on crypt fission as the mechanism for the more rapid evolution of wholly mutated crypts in the colon. The hypothesis should enable us to predict the results of future experiments, namely that the emergence of wholly mutated crypts is proportional to the crypt fission index.