Gene Targeting Reveals a Crucial Role forMTG8 in the Gut

Abstract

The MTG8 (ETO) locus is involved in a reciprocal exchange with runx1 in the t(8;21) of acute myeloid leukemia. It is a member of a small gene family encoding transcriptional regulators that interact with corepressors and histone deacetylase. However, the physiologic cellular processes controlled byMTG8 are not known. In order to gain an insight into the latter, we have generated mutant mice with an insertional inactivation at the locus, which disrupts transcription of exon 2. The postnatal viability of homozygous mutants was greatly reduced. In approximately 25% the midgut was missing, whereas practically all pups surviving past the first 2 days showed severe growth impairment, which was likely due to a gross disruption of the gut architecture. The latter phenotype could be traced back to late embryonic development. No difference in gut cell differentiation or proliferation was found compared to wild-type littermates. Levels of factors known to be involved in gut morphogenesis were also unchanged. MTG8 is expressed in the outermost layers of the developing gut from at least E9.5. Thus, MTG8 plays a novel, essential role in the gastrointestinal system.

ACKNOWLEDGMENTS

We are particularly grateful to Terence Rabbitts for constant encouragement and strategic advice. We also thank Vania Cilli for help in the isolation of mouse MTG8 genomic clones, Dallas Swallow for the gift of the anti-human sucrase-isomaltase monoclonal antibody, Andy Copp and Patrizia Ferretti for comments, and the staff of the Royal Veterinary College, London, England, for expert mouse husbandry.

This work was supported by MRC PG9311737.