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Atoh1 is a basic helix-loop-helix transcription factor that is essential for the formation of intestinal secretory cells (goblet, Paneth, and enteroendocrine cells).
We have studied the role of Atoh1 in regulating normal intestinal function and response to pathological states by generating mice with an intestine-specific ablation of Atoh1.
Our recent studies demonstrate that Atoh1 functions as a tumor suppressor in the colon, where its expression is silenced in ~80% of sporadic colon cancers. We modeled this in using the intestine-specific Atoh1 mutant mice and discovered that they develop 10-14 times more colon tumors than control mice that retain Atoh1 expression.
Current projects will determine the mechanism by which Atoh1 functions as a tumor suppressor, and how this gene can be targeted to develop new cancer therapies.
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(Left) Small intestine and (Right) colon from Atoh1lacZ mice, in which the lacZ gene encoding bacterial β-galactosidase replaced the endogenous Atoh1 gene, stained with Xgal for β-galactosidase expression. Cells marked in blue express β-galactosidase from the endogenous Atoh1 locus. Goblet, Paneth, and enteroendocrine cells of the intestinal epithelium are marked, but none of the absorptive enterocytes or underlying mesenchymal cells express β-galactosidase.
Mice with intestine-specific ablation of Atoh1 (Atoh1∆intestine) were crossed to APCmin mice which normally develop few colon tumors. 50% of control APCmin; Atoh1WT mice developed colon tumors, on average 1 tumor per mouse (white bars in graphs; histologic section shown at top left). 100% of APCmin; Atoh1∆intestine double mutant mice developed colon tumors, on average 12 tumors per mouse (black bars in graphs; histologic section shown at bottom left).
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