NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

Abstract

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1⁺/NKX6.1⁺), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1⁺/NKX6.1^-) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

Keywords: Cell therapy; Diabetes; Pancreatic progenitors; Pluripotent stem cells; Transcription factor; β cell mass.

Fig. 1

Schematic representation showing the development of the pancreas from foregut endoderm into pancreatic islet. Tip and trunk domain formation and segregation during the primary transition. During the secondary transition, the formed trunk domain (green) gives rise to the endocrine progenitors and subsequently pancreatic islets, while the tip domain (purple) develops to the exocrine progenitors expressing PTF1A

Fig. 2

The expression of key transcription factors (TFs) during different stages of multipotent pancreatic progenitor (MPC) differentiation into different lineages of pancreatic cells. NKX6.1 expression starts at the MPC stage, continues in the endocrine lineage, and becomes restricted to β cells

Fig. 3

Schematic representation showing the function of NKX6.1 during early and late pancreatic development

Fig. 4

Function of NKX6.1 in adult mouse pancreatic β cells. Nkx6.1 regulates the expression of genes encoding for proteins responsible for β cell proliferation (Ccnd2, Glut2, AURKA, c-Fos, Nr4a1, and Nr4a3), β cell development and function (MafA, Mnx1, Rfx6, and Tle3), glucose uptake and metabolism (Glut2, G6pc2, Pcx), and insulin biosynthesis (Ero1lb and Slc30a8)

Fig. 5

Structural architecture and domain organization of NKX6.1. A schematic representation of NKX6.1, consists of N-terminal repression domain (N), a DNA-binding homeodomain, and a C-terminal activation domain (C). Crystal structure of Aristaless and Clawless homeodomains of drosophila in complex with the DNA (PDBID: 3A01). The two homeodomains (orange and cyan) cooperate in binding onto the DNA (gray). The drosophila homeodomain structure is the closest to NKX6.1 homeodomain