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.

Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?

“…However, the endocrine cells that were generated were mainly polyhormonal (e.g., insulin and glucagon co-expressing cells) that are more akin to immature islet cells [ 49 ]. The resulting insulin-expressing cells also lacked the essential beta cell transcription factors NKX6.1 and PDX1 [ 50 ]. Over the ensuing years, strategies have been devised and optimized in order to generate monohormonal insulin-expressing cells that co-express NKX6.1 and PDX1 by modifying the composition and timing of growth factor and small molecule addition [ 51 , 52 , 53 ].…”

“…Monogenic forms of diabetes are caused by mutations in genes that are involved in beta cell development, function, and survival [ 50 , 133 ]. Several groups have compared monogenic diabetes patients’ and healthy controls’ iPSC-derived beta cells.…”

The making of insulin in health and disease

“…Glucose stimulates the activity of insulin transcription factors pancreatic and duodenal homeobox 1 (PDX-1), neurogenic differentiation 1 (NEUROD1)-E47 and MafA at multiple levels, including changes in their expression levels, subcellular localisation, DNA-binding activity, transactivation capability and interactions with other proteins. For more information on this topic, we refer readers to another review within this special issue [14]. However, for the specific purpose of this article, it is critical to emphasise that the levels of preproinsulin (i.e.…”

PDX1 directs a core developmentally and evolutionarily conserved gene program in the pancreatic islet

“…Mutations of key transcription factors cause defects in the endocrine pancreas development and impose susceptibility for diabetes (2). One of the well-studied transcription factors and diabetes genes, pancreatic and duodenal homeobox 1 ( PDX1 ), plays essential roles in pancreas organogenesis, endocrine pancreas development, and in the growth and function of insulin-secreting beta cells in both mouse and human (3, 4).…”