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

L. Sussel, J. Kalamaras, Dennis Hartigan-O'Connor, J. J. Meneses, R. A. Pedersen, J. L R Rubenstein, M. S. German

Research output: Contribution to journalArticle

470 Citations (Scopus)

Abstract

The endocrine pancreas is organized into clusters of cells called islets of Langerhans comprising four well-defined cell types: α, β, δ 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 α, β and PP cells, but not in δ 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 β cells and have fewer glucagon-producing α 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 β cell markers, such as islet amyloid polypeptide and Pdx1, but lack other definitive β cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2.2 is required for the final differentiation of pancreatic β cells, and in its absence, β cells are trapped in an incompletely differentiated state.

Original languageEnglish (US)
Pages (from-to)2213-2221
Number of pages9
JournalDevelopment
Volume125
Issue number12
StatePublished - 1998
Externally publishedYes

Fingerprint

Cell Differentiation
Transcription Factors
Islets of Langerhans
Pancreas
Islet Amyloid Polypeptide
Facilitative Glucose Transport Proteins
Homeobox Genes
Glucagon
Hyperglycemia
Embryonic Structures
Parturition
Hormones
Insulin
Mutation

Keywords

  • β cells
  • Diabetes
  • Nkx2.2
  • Pancreas
  • Transcription factors

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Sussel, L., Kalamaras, J., Hartigan-O'Connor, D., Meneses, J. J., Pedersen, R. A., Rubenstein, J. L. R., & German, M. S. (1998). Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells. Development, 125(12), 2213-2221.

Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells. / Sussel, L.; Kalamaras, J.; Hartigan-O'Connor, Dennis; Meneses, J. J.; Pedersen, R. A.; Rubenstein, J. L R; German, M. S.

In: Development, Vol. 125, No. 12, 1998, p. 2213-2221.

Research output: Contribution to journalArticle

Sussel, L, Kalamaras, J, Hartigan-O'Connor, D, Meneses, JJ, Pedersen, RA, Rubenstein, JLR & German, MS 1998, 'Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells', Development, vol. 125, no. 12, pp. 2213-2221.
Sussel, L. ; Kalamaras, J. ; Hartigan-O'Connor, Dennis ; Meneses, J. J. ; Pedersen, R. A. ; Rubenstein, J. L R ; German, M. S. / Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells. In: Development. 1998 ; Vol. 125, No. 12. pp. 2213-2221.
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