Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

Abstract

Lineage tracing studies have revealed that transcription factors play a cardinal role in pancreatic development, differentiation and function. Three transitions define pancreatic organogenesis, differentiation and maturation. In the primary transition, when pancreatic organogenesis is initiated, there is active proliferation of pancreatic progenitor cells. During the secondary transition, defined by differentiation, there is growth, branching, differentiation and pancreatic cell lineage allocation. The tertiary transition is characterized by differentiated pancreatic cells that undergo further remodeling, including apoptosis, replication and neogenesis thereby establishing a mature organ. Transcription factors function at multiple levels and may regulate one another and auto-regulate. The interaction between extrinsic signals from non-pancreatic tissues and intrinsic transcription factors form a complex gene regulatory network ultimately culminating in the different cell lineages and tissue types in the developing pancreas. Mutations in these transcription factors clinically manifest as subtypes of diabetes mellitus. Current treatment for diabetes is not curative and thus, developmental biologists and stem cell researchers are utilizing knowledge of normal pancreatic development to explore novel therapeutic alternatives. This review summarizes current knowledge of transcription factors involved in pancreatic development and b-cell differentiation in rodents.

Modelling of pancreatic cancer biology: transcriptomic signature for 3D PDX-derived organoids and primary cell line organoid development

“…Interestingly, PDX1 expression was low in CLOs compared to 2D primary cell lines. PDX1 is a transcription factor which is essential for pancreatic development and differentiation of all pancreatic cell lineages 42 . The over expression of PDX1 in PDAC highlighted its role as an oncogene 43 .…”

Understanding human fetal pancreas development using subpopulation sorting, RNA sequencing and single-cell profiling

“…Another example is represented by the transcription factor NKX2-2, which is expressed in rodents by early pancreatic progenitors upstream of NEUROG3, whereas its onset is downstream of NEUROG3 in humans (Jennings et al, 2013). Many genes acting downstream of NEUROG3, some of which are direct targets, have been identified in the mouse (Dassaye et al, 2016). Some control endocrine differentiation in all endocrine cell types, whereas others are specific to one or to several subtypes.…”

Generative modeling of single-cell population time series for inferring cell differentiation landscapes

“…We also show that PTF1A and HES1 overexpression result in the opposite effect ( Figure 5c). We observed corresponding decreases in endocrine and exocrine cell proportions with knock-downs of NEUROG3/NKX6.1 and PTF1A/HES1, respectively ( Figure S5a-b) We next simulated the effects of TFs involved in the specification of cell types post-endocrine induction, where ARX and PAX4 have previously been shown to have an antagonistic effect on the specification of endocrine precursors to α and β-cell fate respectively (Dassaye et al, 2016). These TFs have been shown to have a reciprocal repressive effect via direct interaction with their respective promoters.…”

“…We first hypothesized that PRESCIENT should be able to recapitulate the effects on cell fate when perturbing transcription factors known to be involved in the regulation of endocrine induction and specification in the starting population (Figure 5a-b). In endocrine/exocrine induction, previous work has shown that NEUROG3 and NKX6 activation is associated with the endocrine lineage, while PTF1A and HES1 is associated with the exocrine lineage (Dassaye et al, 2016;Gradwohl et al, 2000;Johansson et al, 2007;van der Meulen and Huising, 2015).…”