Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells

Abstract

The endocrine pancreas is organized into clusters of cells called islets of Langerhans comprising four well-defined cell types: alpha beta, delta and PP cells. While recent genetic studies indicate that islet development depends on the function of an integrated network of transcription factors, the specific roles of these factors in early cell-type specification and differentiation remain elusive. Nkx2.2 is a member of the mammalian NK2 homeobox transcription factor family that is expressed in the ventral CNS and the pancreas. Within the pancreas, we demonstrate that Nkx2.2 is expressed in alpha, beta and PP cells, but not in delta cells. In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth. Immunohistochemical analysis reveals that the mutant embryos lack insulin-producing beta cells and have fewer glucagon-producing alpha cells and PP cells. Remarkably, in the mutants there remains a large population of islet cells that do not produce any of the four endocrine hormones. These cells express some beta cell markers, such as islet amyloid polypeptide and Pdx1, but lack other definitive beta cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2.2 is required for the final differentiation of pancreatic beta cells, and in its absence, beta cells are trapped in an incompletely differentiated state.

REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

“…Genetic experiments have indeed revealed numerous transcriptional regulators that promote pancreatic endocrine cell formation, including NKX6-1, NKX2-2, NEU-ROG3, HNF1B, and INMS1, among others (Sussel et al 1998;Gradwohl et al 2000;Osipovich et al 2014;De Vas et al 2015). Among DNA binding factors that suppress endocrinogenesis, Hippo-responsive TEAD-YAP complexes are an integral component of pancreatic multipotent progenitor enhancers and plausibly counteract endocrine differentiation by promoting a progenitor transcriptional state (Cebola et al 2015;Mamidi et al 2018;Rosado-Olivieri et al 2019).…”

“…Cellular programming and differentiation result from an interplay of positive and negative transcriptional regulatory mechanisms (Crews and Pearson 2009;Graf and Enver 2009). Several DNA binding transcription factors are known to promote endocrine differentiation during pancreas development (Sussel et al 1998;Gradwohl et al 2000;Osipovich et al 2014;De Vas et al 2015). A more limited number of transcriptional regulators, such as HES1 and TEAD-YAP, have been shown to exert negative endocrine regulation (Jensen et al 2000;Cebola et al 2015;Mamidi et al 2018).…”

Goldfish adipocytes are pancreatic beta cell‐like, glucose‐responsive insulin‐producing cells

“…Nkx2.2, a member of the NK family of homeodomain proteins expressed in the early embryonic pancreatic epithelium, is necessary for the β-cells to differentiate fully to mature, insulin-producing cells (Sussel et al, 1998). The paired-homeodomain factor Pax6 functions in the final steps of islet-cell differentiation and is critical to the development and maintenance of the final differentiated islet-cell phenotypes (Wilson et al, 2003).…”

GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

“…This is possibly due to subtle delays in human pancreas development compared to mice, preventing early differentiation of endocrine cells. Additionally, human endocrine progenitor cells lack the expression of NKX2.2 , a transcription factor that is critical for beta cell development in mice [ 84 ]. Unfortunately, due to a lack of available antibodies, we do not know the expression of GLIS3 during human pancreatic development.…”