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Transgenic overexpression of Neurogenin 3 in the intestine promotes endocrine cell development to the detriment of goblet cells

Transgenic mice expressing Neurogenin 3 (Ngn3) in the intestinal epithelium were generated using the villin promoter (Vil) to test whether this transcription factor promotes enteroendocrine cell differentiation. Founders were analyzed at embryonic day 18.5 for specific cell lineages using histological methods and measuring marker gene expression by quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR). Analysis was focused on the three highest expressing transgenics: 71, 76 and 179. There was a marked increase in cells that immunostained for the pan‐endocrine marker chromogranin A. This was confirmed by qRT‐PCR with a 16‐ and 9‐fold increase in transgenics 71 and 179, respectively. Staining for specific hormone products revealed that cholecystokinin‐ and serotonin‐producing cells were increased. Hormone upregulation was confirmed by qRT‐PCR, including cholecystokinin, secretin, somatostatin and the serotonin converting enzyme tryptophan hydrogenase 1, demonstrating a general enhancement in enteroendocrine development. Accordingly the proendocrine transcription factors NeuroD1 and Pax4 also showed increased expression. Expansion of endocrine cells depleted other secretory cells, as demonstrated by fewer goblet cells. Thus, Ngn3 is sufficient to promote a program of endocrine cell development by redirecting secretory precursors into the endocrine lineage.