The Drosophila posterior midgut is closely analogous to the mammalian small intestine; the midgut epithelium is maintained by frequent division of self-renewing intestinal stem cells (ISCs). Development of differentiated absorptive and secretory gut cell types requires Notch signaling; loss of Notch (N) function in the posterior midgut results in stem cell tumor formation. Tumor growth correlates with an expansion of tracheal cell branching, similar to increased angiogenesis observed for human cancers.
Up to 10% of aged wild-type males are found to have at least one stem-cell tumor in the gut. Since N is sex-linked, Drosophila males are susceptible to effects of spontaneous somatic loss of the N gene. Many of the spontaneous tumors were shown to have genetic lesions that affected the Notch region.
This system has been used with targeted RNAi-effected loss of N expression in the ISCs to investigate triggers for and downstream effectors of stem cell tumorigenesis. Depletion of Notch causes multilayered midgut tumors populated by excess progenitor and enteroendocrine cells. Notch-defective ISC tumors have also been generated by tissue-specific CRISPR/Cas9 mutagenesis.
In contrast to intestines with a conventional microbiome, tumors rarely appear in Notch-depleted intestinal stem cells in age-matched, germ-free flies. This observation led to investigation of the role of the commensal bacterial species Lactobacillus brevis in the course of ISC tumorigenesis in flies.
[updated Jan. 2022 by FlyBase; FBrf0222196]
Many to one: 4 human genes to 1 Drosophila gene.
Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3, NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 43-44% identity and 56-57% similarity with NOTCH1 and NOTCH2.