Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

Abstract

In recent years major progress has been made in understanding the role of transcription factors in the development of the endocrine pancreas in the mouse. Here we describe how a number of these transcription factors play a role in maintaining the differentiated phenotype of the β cell, and in the mechanisms that allow the β cell to adapt to changing metabolic demands that occur throughout life. Amongst these factors, Pdx1 plays a critical role in defining the region of the primitive gut that will form the pancreas, Ngn3 expression drives cells towards an endocrine lineage, and a number of additional proteins including Pdx1, in a second wave of expression, Pax4, NeuroD1/β2, and MafA act as β cell differentiation factors. In the mature β cell Pdx1, MafA, β2, and Nkx2.2 play important roles in regulating expression of insulin and to some extent other genes responsible for maintaining β cell function. We emphasise here that data from gene expression studies in rodents seldom map on to the known structure of the corresponding human promoters. In the adult the β cell is particularly susceptible to autoimmune mediated attack and to the toxic metabolic milieu associated with over-eating, and utilises a number of these transcription factors in its defence. Pdx1 has anti-apoptotic and proliferative activities that help facilitate the maintenance of β cell mass, while Ngn3 may be involved in the recruitment of progenitor cells, and Pax4 (and possibly HNF1α and Hnf4α) in the proliferation of β cells in the adult pancreas. Other transcription factors with a more widespread pattern of expression that play a role in β survival or proliferation include Foxo1, CREB family members, NFAT, FoxM1, Snail and Asc-2.2

Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells

“…The marked up-regulation of these important transcription factors fits well with the observation here that visfatin causes an increase in insulin secretion (Fig. 2), as they are both thought to be involved in insulin gene transcription (Bernardo et al 2008). Significant increases were also observed in some unexpected genes, including CD28 (a 97-fold increase).…”

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

“…The mature beta cell phenotype is commonly defined by the expression of genes such as the insulin gene, Pdx1, Glut2, Mafa, Neurod1, glucokinase and Nkx6-1 [36]. In our activin A-treated cells, genes associated with beta cell maturity, specifically Ins1, Ins2, Pdx1, Glut2, Nkx6-1 and Mafa were downregulated.…”

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

“…PAX4 functions as a transcription repressor and plays a crucial role in pancreatic beta cell function and development [27]. It also plays a role in beta cell proliferation and survival [28,29]. Heterozygous Pax4-knockout mice harbour less mature pancreatic beta and delta cells, but have numerous abnormally clustered alpha cells, indicating the essential role of PAX4 in the differentiation of beta and delta cell lineages [30].…”