Transcription factors that shape the mammalian pancreas

Abstract

Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know about mammalian pancreas development stems from mouse genetics. We have learnt that a unique set of transcription factors controls endocrine and exocrine cell differentiation. Transgenic mouse models have been instrumental in studying the function of these transcription factors. Mouse and human pancreas development are very similar in many respects, but the devil is in the detail. To unravel human pancreas development in greater detail, in vitro cellular models (including directed differentiation of stem cells, human beta cell lines and human pancreatic organoids) are used; however, in vivo validation of these results is still needed. The current best 'model' for studying human pancreas development are individuals with monogenic forms of diabetes. In this review, we discuss mammalian pancreas development, highlight some discrepancies between mouse and human, and discuss selected transcription factors that, when mutated, cause permanent neonatal diabetes. Graphical abstract.

Keywords: Development; Human; Islets of Langerhans; Mouse; NEUROG3; Neonatal diabetes; Neurogenin 3; PDX1; Pancreas and duodenal homeobox 1; RFX6; Regulatory factor X6; Review; Transcription factors.

Graphical abstract

Fig. 1

Developmental classification of permanent neonatal diabetes. Transcription factors control normal human pancreas development, from its morphogenesis, through endocrine differentiation, to beta cell development and function. Mutations in transcription factor genes such as PDX1, NEUROG3 and RFX6 are responsible for different forms of permanent neonatal diabetes, thus, neonatal diabetes could be classified according to the developmental impact of the transcription factor mutations on pancreas, islet or beta cell formation. Mutations in genes that encode proteins involved in the machinery of insulin secretion (ABCC8, KCNJ11) or insulin (INS) itself can also be included in such a developmental classification. Colour scale indicates mutation severity from null (red) to hypomorphic (blue). This figure was created using Servier Medical Art (https://smart.servier.com/). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. This figure is available as a downloadable slide