Low levels of Grainy head isoforms regulate Drosophila midgut intestinal stem cell differentiation

Regeneration of the Drosophila midgut epithelium depends upon differential expression of transcription factors in intestinal stem cells and their progeny. The grainy head locus produces multiple splice forms that result in production of two classes of transcription factor, designated Grh.O and Grh.N. grainy head is expressed at very low levels in the midgut and yet Grh.O is required for maintenance of intestinal stem cells and exhibits a second function regulating enteroblast differentiation in conjunction with miR-8 and Zfh-1. Grh.O expression must be tightly regulated as high level ectopic expression in enteroblasts results in cells with confused identity and promotes excess proliferation in the epithelium. Expression of Grh.N in intestinal stem cells promotes differentiation to enterocytes. Thus midgut regeneration is not only dependent upon signalling pathways that regulate transcription factor expression, but also upon regulated mRNA splicing of these genes. This study also indicates that networks of transcription factors are acting at very low levels to regulate stem cell maintenance and differentiation.