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

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
Proc Natl Acad Sci U S A. 2012 109 (19): 7356-61

PMID: 22529374 · PMCID: PMC3358874 · 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.

MeSH Terms (26)

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

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