Mind bomb 1 is required for pancreatic β-cell formation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-05, Vol.109 (19), p.7356-7361
• Main Authors: Horn, Signe, Kobberup, Sune, Jørgensen, Mette C, Kalisz, Mark, Klein, Tino, Kageyama, Ryoichiro, Gegg, Moritz, Lickert, Heiko, Lindner, Jill, Magnuson, Mark A, Kong, Young-Yun, Serup, Palle, Ahnfelt-Rønne, Jonas, Jensen, Jan N
• Format: Article
• Language: English
• Subjects: Acinar cells; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Sciences; Blotting, Western; Cell Lineage; Developmental biology; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryonic stem cells; Embryos; Endocrine cells; Female; Gene Expression Regulation, Developmental; genes; Hepatocyte Nuclear Factor 1-beta - genetics; Hepatocyte Nuclear Factor 1-beta - metabolism; Hepatocyte Nuclear Factor 3-beta - genetics; Hepatocyte Nuclear Factor 3-beta - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural stem cells; Neurons; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pancreas; Pancreas - cytology; Pancreas - embryology; Pancreas - metabolism; Progenitor cells; Receptors, Notch - genetics; Receptors, Notch - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stem cells; Time Factors; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; transcriptional activation; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1203605109

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.