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Mind bomb 1 is required for pancreatic β-cell formation.

During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1(+)Ptf1a(+) multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1(-)Ptf1a(+) acinar progenitors and proximal Nkx6-1(+)Ptf1a(-) duct and β-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing β-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of β-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and β-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1β(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and β-cells. An accompanying increase in Nkx6-1(-)Ptf1a(+) and amylase(+) cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed β-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate β-cell formation.

Pubmed ID: 22529374

Authors

  • Horn S
  • Kobberup S
  • Jørgensen MC
  • Kalisz M
  • Klein T
  • Kageyama R
  • Gegg M
  • Lickert H
  • Lindner J
  • Magnuson MA
  • Kong YY
  • Serup P
  • Ahnfelt-Rønne J
  • Jensen JN

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 8, 2012

Associated Grants

  • Agency: European Research Council, Id: 242807
  • Agency: NIDDK NIH HHS, Id: DK072495
  • Agency: NIDDK NIH HHS, Id: DK20593
  • Agency: NIDDK NIH HHS, Id: U01 DK072473

Mesh Terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • Cell Lineage
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental
  • Hepatocyte Nuclear Factor 1-beta
  • Hepatocyte Nuclear Factor 3-beta
  • Homeodomain Proteins
  • Insulin-Secreting Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Pancreas
  • Receptors, Notch
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Time Factors
  • Transcription Factors
  • Ubiquitin-Protein Ligases