NGN3

Neurogenin-3 (Ngn3) is a vertebrate basic helix-loop-helix transcription factor encoded by the NEUROG3 gene in humans. It is a member of the proneural bHLH family and plays a pivotal role in the development of endocrine cells in the pancreas and intestine.

In the developing pancreas, Ngn3 is expressed transiently in a subset of endocrine progenitor cells derived from the pancreatic epithelium during the secondary transition. Its expression commits progenitors to the endocrine lineage and is required for the formation of all mature islet cell types, including alpha, beta, delta, PP, and epsilon cells. In the intestine, Ngn3 marks endocrine progenitors of the enteroendocrine lineage, which differentiate into various hormone-producing cells that regulate gut physiology.

Regulation of Ngn3 involves Notch signaling, which negatively regulates its expression to maintain progenitors. When Notch signaling is reduced or interrupted, Ngn3 promotes endocrine differentiation. Downstream targets include NeuroD1 and other endocrine markers, placing Ngn3 at the top of a transcriptional cascade that initiates endocrine development.

Clinical relevance of Ngn3 is highlighted by knockout and human mutation studies. In mice, loss of Ngn3 prevents formation of pancreatic and intestinal endocrine cells, resulting in severe metabolic and digestive dysfunction. In humans, pathogenic variants in NEUROG3 can cause congenital diarrheal disease with neonatal diabetes due to a lack of enteroendocrine and insulin-producing cells.

Applications of Ngn3 knowledge extend to stem cell and organoid research, where transient or forced NGN3 expression is used to drove endocrine differentiation from pluripotent or progenitor cells, with the aim of generating beta-like cells for diabetes research, though achieving complete functional maturation remains an area of ongoing study.