Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells

Abstract

ObjectiveThe transcription factors (TF) Foxa2 and Pdx1 are key regulators of beta-cell (β-cell) development and function. Mutations of these TFs or their respective cis-regulatory consensus binding sites have been linked to maturity diabetes of the young (MODY), pancreas agenesis, or diabetes susceptibility in human. Although Foxa2 has been shown to directly regulate Pdx1 expression during mouse embryonic development, the impact of this gene regulatory interaction on postnatal β-cell maturation remains obscure.MethodsIn order to easily monitor the expression domains of Foxa2 and Pdx1 and analyze their functional interconnection, we generated a novel double knock-in homozygous (FVFPBFDHom) fluorescent reporter mouse model by crossing the previously described Foxa2-Venus fusion (FVF) with the newly generated Pdx1-BFP (blue fluorescent protein) fusion (PBF) mice.ResultsAlthough adult PBF homozygous animals exhibited a reduction in expression levels of Pdx1, they are normoglycemic. On the contrary, despite normal pancreas and endocrine development, the FVFPBFDHom reporter male animals developed hyperglycemia at weaning age and displayed a reduction in Pdx1 levels in islets, which coincided with alterations in β-cell number and islet architecture. The failure to establish mature β-cells resulted in loss of β-cell identity and trans-differentiation towards other endocrine cell fates. Further analysis suggested that Foxa2 and Pdx1 genetically and functionally cooperate to regulate maturation of adult β-cells.ConclusionsOur data show that the maturation of pancreatic β-cells requires the cooperative function of Foxa2 and Pdx1. Understanding the postnatal gene regulatory network of β-cell maturation will help to decipher pathomechanisms of diabetes and identify triggers to regenerate dedifferentiated β-cell mass.

Exome sequencing identifies a de novo FOXA2 variant in a patient with syndromic diabetes

“…Postnatally, Foxa2 regulates beta‐cell maturation, maintains beta‐cell function, and is involved in insulin exocytosis. Therefore, a FOXA2 gene defect could lead to an early dysregulated insulin response, and then, progressive loss of beta‐cell function, consistent with neonatal hypoglycemia and childhood‐onset diabetes . In addition, Foxa2 influences the expression of genes involved in congenital hyperinsulinism and monogenic diabetes , including GCK , HNF4A , HNF1A , KCNJ11 , and ABCC8.…”

“…Therefore, a FOXA2 gene defect could lead to an early dysregulated insulin response, and then, progressive loss of beta-cell function, consistent with neonatal hypoglycemia and childhood-onset diabetes. 6 In addition, Foxa2 influences the expression of genes involved in congenital hyperinsulinism and monogenic diabetes, including GCK, HNF4A, HNF1A, KCNJ11, and ABCC8. 7 In mice, a beta-cell specific homozygous deletion of Foxa2 led to hypoglycemia, a dysregulated insulin response to glucose, and death before weaning.…”

Animal models of obesity and diabetes mellitus

“…A similar phenotype to that of MODYs occurs in Foxa2-Venus Fusion (FVF), Pdx1-BFP Fusion (PBF) double homozygous (FVFPBF DHom ) reporter mice, in which Foxa2 and Pdx1 are genetically fused with fluorescent proteins. In these mice, impaired β-cell maturation and loss of identity trigger transdifferentiation of β-cells into other endocrine cell types that consequently decreases β-cell number and causes diabetes 279 .…”

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

“…Pancreas/duodenum homeobox protein 1 (PDX1) is the master transcription factor that controls pancreatic β cell maturation and function by regulating the expression of several key genes including glucokinase and insulin genes, and a decrease in PDX1 expression is the key characteristics of pancreatic β dysfunction. 21,22 Transcription factor forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3β), is also critical for maintaining pancreatic cell functions by regulating PDX1 expression. [23][24][25][26][27] Glucose-induced DNA methylation in the promoter region and miRNAs such as miR-141, miR-124a, and miR-342 inhibit FOXA2 expression in pancreatic β cells.…”